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Clinical trials landscape

TL;DR — The CKD trial landscape has moved from albuminuria and short eGFR change toward sustained decline, kidney failure and cardiovascular death, but surrogate endpoints remain common in small or rare-disease studies. DAPA-CKD, EMPA-KIDNEY, CREDENCE, FIDELIO-DKD and FLOW provide completed outcome anchors (Heerspink 2020, PMID 32970396) (EMPA-KIDNEY Collaborative Group 2023, PMID 36331190) (Perkovic 2019, PMID 30990260) (Bakris 2020, PMID 33264825) (Perkovic 2024, PMID 38785209). Live ClinicalTrials.gov queries on 2026-10-11 and 2026-10-18 show current work on potassium-enabled RAS optimization, advanced-CKD SGLT2 inhibition, screening implementation, paediatric finerenone and cognition. EASi-KIDNEY (NCT06531824) has closed recruitment with an actual enrolment of 8,371 against the 11,000 planned, and lists an estimated primary completion of 2026-12-31; PROTECT (NCT03762850) is now completed; ZEUS (NCT05021835) is completed at 6,385 with no results posted; the adaptive platform trial (NCT06058585) now lists enrolment of 2,000. The non-diabetic finerenone question has been answered rather than remaining open: FIND-CKD (NCT05047263) is complete and published (Heerspink 2026, PMID 42246672), as are CONFIDENCE (NCT05254002) and FINE-ONE (NCT05901831) (Agarwal 2025, PMID 40470996) (Heerspink 2026, PMID 41780000). Registry status is operational metadata, not proof of efficacy.

Completed outcome platform

DAPA-CKD and EMPA-KIDNEY broadened SGLT2 evidence beyond diabetes (Heerspink 2020, PMID 32970396) (EMPA-KIDNEY Collaborative Group 2023, PMID 36331190). FIDELIO/FIGARO and FLOW were diabetic-CKD programs (Agarwal 2022, PMID 35023547) (Perkovic 2024, PMID 38785209); both classes have since reported beyond that population — finerenone in FIND-CKD and its glomerular-disease subgroup, and semaglutide in a pooled SELECT/FLOW/SOUL analysis that includes participants without diabetes (Heerspink 2026, PMID 42246672) (Neuen 2026, PMID 42246414) (Mann 2026, PMID 42567173).

Cause-specific platform

NefIgArd and PROTECT represent the shift to targeted IgA-nephropathy trials (Lafayette 2023, PMID 37591292) (Rovin 2023, PMID 37931634). FSGS shows why proteinuria and GFR endpoints can diverge (Rheault 2023, PMID 37921461).

Implementation trials

Screening and app-supported pathways test whether evidence reaches undiagnosed populations; their endpoints should include treatment initiation and equity, not testing yield alone.

Combination trials

The gap has narrowed but not closed. CONFIDENCE (NCT05254002) randomized 779 people with type 2 diabetes and CKD 1:1:1 to finerenone, empagliflozin or both, and combination therapy lowered uACR 29% more than finerenone alone and 32% more than empagliflozin alone at day 180 (Agarwal 2025, PMID 40470996). It is a phase 2 albuminuria trial covering two of four classes, so the missing design remains a strategy or factorial randomization across RAS, SGLT2, MRA and GLP-1 layers powered for kidney failure and death; current modelling cannot identify sequence (Neuen 2024, PMID 37952217). An NHANES microsimulation of 8,152 US adults found 19% already on a RAS inhibitor, 1% on an SGLT2 inhibitor, 1% on a GLP-1 receptor agonist and none on a non-steroidal MRA; dual RAS+SGLT2 eligibility was 15% overall (84% of the diabetes-plus-CKD subgroup) and quadruple-therapy eligibility 4% overall (40% of diabetes-plus-CKD). Under the model's assumptions, triple RAS+SGLT2+GLP-1 therapy was projected to avert about twice as many deaths as dual RAS+SGLT2 despite slightly lower eligibility (Nardone 2026, PMID 42853614). Eligibility and modelled deaths averted are not randomized sequence evidence.

Registry cautions

Recruiting status changes; eligibility and outcome definitions require record-level review. This page records a dated snapshot only.

Border

Dialysis-device and transplant-immunology pipelines are excluded unless they alter the decision, timing or patient-important outcome.

ClinicalTrials.gov snapshot

Every identifier and status below was re-queried through the ClinicalTrials.gov v2 API on 2026-11-01. Against the 2026-10-25 snapshot: VIDEO-KD (NCT04347629) moved ACTIVE_NOT_RECRUITING → COMPLETED (completion 2026-05-31); FINE-ONE (NCT05901831) posted registry results on 2026-10-27 (UACR ratio 0.66 vs 0.88, matching the published 0.75 treatment ratio; PMID 41780000). ZEUS, EASi-KIDNEY, VISIONARY, RAINIER and I CAN still have no posted results. Newly tracked: NCT05510115 (ADPKD empagliflozin feasibility).

NCT ID Study Status at query CKD question
NCT03036150 DAPA-CKD COMPLETED Dapagliflozin kidney/CV outcomes
NCT03594110 EMPA-KIDNEY COMPLETED Empagliflozin across broad CKD
NCT02065791 CREDENCE COMPLETED Canagliflozin in diabetic nephropathy
NCT02540993 FIDELIO-DKD COMPLETED Finerenone, kidney-primary diabetic CKD
NCT02545049 FIGARO-DKD COMPLETED Finerenone, cardiovascular-primary diabetic CKD
NCT03819153 FLOW COMPLETED Semaglutide kidney outcomes in T2D CKD
NCT03643965 NefIgArd COMPLETED Targeted-release budesonide in IgA nephropathy
NCT03762850 PROTECT COMPLETED (2026-08-19) Sparsentan in IgA nephropathy
NCT03710291 VALOR-CKD TERMINATED Veverimer and CKD progression
NCT05047263 FIND-CKD COMPLETED Finerenone in non-diabetic CKD — primary results published (PMID 42246672); glomerular-disease subgroup (PMID 42246414)
NCT05254002 CONFIDENCE COMPLETED Finerenone, empagliflozin or both; 180-day albuminuria (PMID 40470996)
NCT05901831 FINE-ONE COMPLETED; registry results posted 2026-10-27 Finerenone in type 1 diabetes and CKD; 6-month albuminuria (PMID 41780000)
NCT05196035 Finerenone paediatric CKD study ACTIVE_NOT_RECRUITING Proteinuric CKD in children
NCT06256991 Potassium correction for RAS optimization RECRUITING Hyperkalaemia as a treatment barrier
NCT07027774 HERO-aCKD NOT_YET_RECRUITING SGLT2 inhibition in advanced non-dialysis CKD
NCT06330480 Check@Home ENROLLING_BY_INVITATION Population screening for CKD and atrial fibrillation
NCT06906640 IRIS-CKD RECRUITING CKD screening/management implementation in diabetes
NCT05970341 Kidney Health: Eat Well, Live Well ACTIVE_NOT_RECRUITING Dietary implementation
NCT04975464 BRINK Memory Study 2.0 ACTIVE_NOT_RECRUITING Cognitive phenotype in kidney disease

The pipeline has moved to combination-on-background-SGLT2

The three largest general-CKD phase 3 programmes below share one design feature: SGLT2 inhibition is in both arms, and the question is what to add. This is a structural change from the 2019–2024 generation, in which SGLT2 inhibitors were the intervention. Smaller programmes still include SGLT2-versus-placebo and non-SGLT2 designs. All records below were retrieved live from the ClinicalTrials.gov API on 2026-10-11.

Trial (NCT) Intervention on background n Status Primary outcome Primary completion
EASi-KIDNEY (NCT06531824) Aldosterone synthase inhibitor BI 690517 (vicadrostat) + empagliflozin vs placebo + empagliflozin 8,371 (actual; 11,000 planned) Active, not recruiting Time to first kidney disease progression, heart-failure hospitalisation, or cardiovascular death 2026-12-31 (estimated)
Baxdrostat + dapagliflozin (NCT06742723) Aldosterone synthase inhibitor baxdrostat + dapagliflozin vs dapagliflozin 5,000 Recruiting ≥50% sustained eGFR decline, kidney failure, heart-failure events, or CV death 2029-12-18
BalanceD-CKD (NCT07624305) Mineralocorticoid receptor modulator balcinrenone + dapagliflozin vs dapagliflozin, CKD stages 3b–4 2,800 Recruiting Time to CV death, kidney-failure death, kidney failure, sustained ≥50% eGFR decline, or heart-failure event 2030-07-01
ZENITH High Proteinuria (NCT06087835) Endothelin A antagonist zibotentan + dapagliflozin vs dapagliflozin 1,835 Active, not recruiting Change in eGFR from baseline 2027-02-18
CKD adaptive platform trial (NCT06058585) Finerenone vs placebo, platform architecture 2,000 Recruiting eGFR slope 2029-12-31
Sotagliflozin in type 1 diabetes DKD (NCT06217302) Sotagliflozin vs placebo 150 Recruiting eGFR after wash-out following treatment period 2028-12

Two aldosterone-synthase inhibitor outcome trials totalling about 13,400 participants (8,371 enrolled in one, 5,000 planned in the other) are the largest single bet in nephrology's current pipeline, and both are explicitly built on top of an SGLT2 inhibitor. They test a hypothesis the finerenone trials could not: whether suppressing aldosterone synthesis rather than blocking its receptor delivers the same or greater kidney protection with a different hyperkalaemia profile. EASi-KIDNEY, which closed at 8,371 rather than its planned 11,000, is event-driven on a hard composite; the baxdrostat trial's inclusion of heart-failure events in the primary composite makes the two results non-interchangeable.

The zibotentan phase 3 is worth flagging for its endpoint choice: change in eGFR from baseline, not a clinical composite (NCT06087835). Given that the ALIGN experience in IgA nephropathy showed the same drug class producing a significant on-treatment eGFR difference and a non-significant one after off-treatment follow-up (PMID 42242268), the specification of the eGFR endpoint will determine what this trial can claim.

Adaptive platform architecture arrives in nephrology

The CKD adaptive platform trial (NCT06058585), sponsored by The George Institute, runs finerenone against placebo within a platform designed to add and drop arms, with eGFR slope as the primary outcome and a listed enrolment of 2,000 (was 1,000 at the 2026-09-02 snapshot). Platform designs have transformed evidence generation in oncology and critical care and have been essentially absent from nephrology, where each drug class has required its own multi-thousand-participant standalone trial. Whether an eGFR-slope-primary platform is accepted by regulators for approval, rather than only for prioritisation, is the open question that determines its impact — and it depends directly on the surrogate-validity literature discussed in definition, staging and measurement.

Questions the pipeline is not asking

Three gaps are visible from the register itself.

  • No head-to-head comparisons of the established classes. CONFIDENCE (PMID 40470996) randomized finerenone and empagliflozin against each of them alone on 180-day albuminuria; nothing in the current phase 3 landscape compares an SGLT2 inhibitor against a GLP-1 receptor agonist or a non-steroidal MRA on hard kidney endpoints.
  • Kidney transplant evidence remains surrogate-based. A 208-person, 12-month randomized trial in chronic allograft dysfunction found no eGFR benefit from dapagliflozin, although proteinuria, blood pressure and weight fell (David-Neto 2026, PMID 42102257). DEAK targets 330 de novo transplant recipients for a three-year chronic-eGFR-slope primary endpoint, with ten-year registry follow-up for cardiovascular events and graft and patient survival (Kongerud 2026, PMID 42315275; NCT05788276). On 2026-10-25 the registry lists ACTIVE_NOT_RECRUITING, estimated primary completion August 2029, and no posted results (NCT05788276). Neither study is powered for graft failure, cardiovascular events or mortality.
  • Non-drug interventions are almost absent at scale. Against about 13,400 participants in two aldosterone-synthase trials, the largest recruiting non-pharmacological CKD trials are an order of magnitude smaller, despite intradialytic exercise producing one of the largest functional effect sizes in the literature (PMID 38320198).

Mechanistic trials that explain the outcome trials

Smaller trials now routinely carry the mechanistic load. The renal mode-of-action study of semaglutide in type 2 diabetes and CKD (NCT04865770, n = 106) has now reported: coprimary MRI outcomes (oxygenation by R2*, global perfusion, and T1-mapped inflammation) were not significantly altered versus placebo at 52 weeks. Secondary signals included a reduced renal-artery resistive index and apparent-diffusion-coefficient stabilization, with transcriptomic effects concentrated in glomerular endothelial cells (Tuttle 2026, PMID 42823485). Pairing an outcome trial with a 106-patient imaging study remains the template; the coprimary null means the hypoxia circuit is still unconfirmed as the mechanism of GLP-1 kidney protection (see pathophysiology and progression).

Aldosterone synthase and mineralocorticoid-receptor modulation now have phase 2 CKD read-outs. Explore-CKD (NCT06150924) randomized 59 adults with uncontrolled hypertension, CKD and albuminuria on RAS blockade and an SGLT2 inhibitor in a four-week crossover to lorundrostat 25 mg/day or placebo: placebo-adjusted automated office systolic blood pressure −7.5 mmHg (−12.3 to −2.7) and UACR −25.6% (−37.7 to −11.2) (Weir 2026, PMID 42778148). MIRO-CKD (NCT06350123) randomized 324 adults with eGFR 25–<60 and UACR 100–5,000 mg/g to balcinrenone 15 or 40 mg plus dapagliflozin 10 mg versus dapagliflozin plus placebo for 12 weeks: week-12 UACR differences versus dapagliflozin alone −22.8% (90% CI −33.3 to −10.7) and −32.8% (−42.0 to −22.1), with investigator-reported hyperkalaemia 6%, 7% and 5% (Heerspink 2025, PMID 41218621). The acute eGFR dip relative to dapagliflozin was small (−0.6 and −1.7 mL/min/1.73 m² at week 4) (Heerspink 2026, PMID 42752537). Neither trial is powered for kidney failure. BalanceD-CKD (NCT07624305, n=2,800, recruiting from 2026-09-01) is the outcome-powered sequel for balcinrenone.

The glomerular-disease pipeline is now larger than the general-CKD pipeline

Where the general-CKD trials (above) test combinations on background SGLT2 inhibition, the glomerular-disease pipeline is testing mechanistically distinct single agents, overwhelmingly against a proteinuria primary endpoint. All records retrieved live from the ClinicalTrials.gov API on 2026-10-11.

Trial (NCT) Target / agent n Condition Primary endpoint Primary completion
NCT05799287 (TELIGAN) Telitacicept (BAFF/APRIL) 318 IgA nephropathy Change in UPCR from baseline 2026-06 (ACTIVE_NOT_RECRUITING; 39-week interim published, PMID 42127391)
NCT06935357 Felzartamab (anti-CD38) 454 IgA nephropathy % change in UPCR from baseline 2027-05-31
NCT07014826 HRS-5965 378 Primary IgA nephropathy Ratio of 24-h UPCR to baseline 2027-10
NCT07390123 HSK39297 370 Primary IgA nephropathy Ratio to baseline in 24-h UPCR at 36 weeks 2027-12
NCT06819826 SC0062 360 IgA nephropathy with proteinuria Change in 24-h UPCR at 36 weeks 2026-12-31
NCT06963827 Mezagitamab 347 IgA nephropathy Change in proteinuria at week 36 2028-09-07
NCT06858319 Zigakibart, open-label extension 220 IgA nephropathy Adverse events 2031-06-25
NCT07220083 BI 764198 286 Focal segmental glomerulosclerosis Relative change in 24-h UPCR at week 104 2028-12-27
NCT05183646 DMX-200 on background ARB 286 FSGS Urine protein/creatinine ratio 2029-12
NCT07213960 APL2 (pegcetacoplan), sequential phase 2/3 270 FSGS Change in log-transformed UPCR 2029-10
NCT04939935 (IMPEDE-PKD) Metformin XR 1,174 ADPKD Change in eGFR 2030-12
NCT07280585 (STOP-PKD) Dapagliflozin 420 ADPKD Chronic eGFR slope 2030-05-15
NCT05373264 Hydrochlorothiazide 300 ADPKD Change in kidney function decline 2030-07

Three observations follow from the register itself.

Proteinuria is carrying almost the entire IgA nephropathy pipeline. Every recruiting phase 3 IgA nephropathy trial listed above has UPCR as its primary endpoint. Given that iptacopan's proteinuria signal did convert to an eGFR slope difference and a kidney-failure hazard ratio of 0.57 (PMID 41910396), while the same class of endpoint in FSGS did not convert (PMID 37921461), the field is placing a large collective bet that the IgA nephropathy translation generalises to other mechanisms within the same disease.

Paediatric extension is now routine and early. Iptacopan (NCT06994845, n=31), ravulizumab (NCT07024563, n=36) and atrasentan (NCT07498335, n=28) all have dedicated paediatric IgA nephropathy studies recruiting — a marked change from a field in which children historically received adult drugs years later without dedicated data.

ADPKD has become a repurposing field. Its three largest recruiting trials test metformin, dapagliflozin and hydrochlorothiazide — none developed for cystic disease — with eGFR-based primary endpoints and completion dates in 2030. After tolvaptan, the pipeline is not novel-mechanism but existing-drug.

IgA-nephropathy phase 3 reports: abstract-verified function and proteinuria

PubMed abstracts for the four October reports are now retrievable. NEJM full text remains subscription-only (Europe PMC: not open access, no PMC copy), so the figures below are abstract-verified and have not been checked against tables, hierarchies or missing-data handling.

Trial / registry 2026-11-01 Publication Abstract-verified result Registry
ORIGIN 3, NCT04716231 Atacicept final (Barratt 2026, PMID 42911181) eGFR slope through week 104 −0.60 vs −5.60 mL/min/1.73 m²/year (difference 5.00, 3.55–6.45); composite 5.1% vs 17.8% (HR 0.24) ACTIVE_NOT_RECRUITING; results first posted 2026-10-01
VISIONARY, NCT05248646 Sibeprenlimab final (Rizk 2026, PMID 42911185) 24-month eGFR slope 0.3 vs −4.2 (difference 4.5, 3.6–5.4); composite 0.4% vs 11.2% (HR 0.029) ACTIVE_NOT_RECRUITING; n=530 listed; no posted results
RAINIER, NCT06564142 Povetacicept 36-week interim (Barratt 2026, PMID 42912669) 24-h uPCR −52.0% vs −4.3% (difference −49.8 points); function outstanding ACTIVE_NOT_RECRUITING; no posted results
I CAN, NCT06291376 Ravulizumab week-34 interim (Barratt 2026, PMID 42912700) 24-h uPCR 43.4% lower than placebo (99% CI 30.1–54.2); eGFR/events outstanding ACTIVE_NOT_RECRUITING; no posted results

A final publication and a registry primary-completion date answer different questions; neither implies that long-term follow-up has ended. Sequence across agents remains untested.

ADPKD SGLT2 feasibility. NCT05510115 randomized 50 adults with rapidly progressive ADPKD, not on tolvaptan, to empagliflozin 25 mg or placebo for 12 months: well tolerated, but height-adjusted total kidney volume rose 10.5%/year versus 5.1% (P=0.001), with no chronic eGFR-slope difference (Seliger 2026, PMID 42925875). The recruiting STOP-PKD dapagliflozin outcome trial (NCT07280585) now has a TKV safety signal to interpret against.

Decision and interpretation matrix

Dimension Question Guardrail
Diagnostic axis Cause + G category + A category Avoid treating eGFR as the diagnosis
Time axis Chronicity and trajectory Separate acute change from persistent disease
Risk axis Kidney failure + cardiovascular events + death Show competing events
Treatment axis Eligibility, absolute benefit, harm, burden Do not rank drugs by relative effect alone
Measurement axis Assay, equation, repeatability State what was actually measured
Equity axis Testing, referral, access, affordability Audit downstream care, not labels only
Patient axis Symptoms, function, life participation Include outcomes patients prioritize
Evidence axis RCT, cohort, model, guideline Do not collapse designs

Evidence ledger

This ledger makes the page’s evidentiary mix inspectable. It does not imply that every source answers every question.

PMID Record used Role and boundary
32970396 Dapagliflozin in Patients with Chronic Kidney Disease. (Heerspink 2020, PMID 32970396) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
36331190 Empagliflozin in Patients with Chronic Kidney Disease. (EMPA-KIDNEY Collaborative Group 2023, PMID 36331190) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
30990260 Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. (Perkovic 2019, PMID 30990260) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
33264825 Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. (Bakris 2020, PMID 33264825) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
38785209 Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. (Perkovic 2024, PMID 38785209) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
35023547 Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. (Agarwal 2022, PMID 35023547) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
37591292 Targeted-release budesonide in primary IgA nephropathy: NefIgArd 2-year results. (Lafayette 2023, PMID 37591292) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
37931634 Sparsentan versus irbesartan in IgA nephropathy: PROTECT 2-year results. (Rovin 2023, PMID 37931634) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
37921461 Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis. (Rheault 2023, PMID 37921461) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
37952217 Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria. (Neuen 2024, PMID 37952217) Modelled projection; the estimate follows from the model inputs and assumptions, not from observed randomized follow-up.
38490803 KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. (KDIGO CKD Work Group 2024, PMID 38490803) Guideline or commentary; recommendation evidence depends on its review.
38519239 Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns. (Levin 2024, PMID 38519239) Guideline or commentary; recommendation evidence depends on its review.
11565518 Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. (Brenner 2001, PMID 11565518) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
11565517 Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. (Lewis 2001, PMID 11565517) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
11565519 The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. (Parving 2001, PMID 11565519) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
18707986 Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk: the ONTARGET study. (Mann 2008, PMID 18707986) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
24206457 Combined angiotensin inhibition for the treatment of diabetic nephropathy. (Fried 2013, PMID 24206457) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
34619108 Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. (Heerspink 2021, PMID 34619108) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
38061371 Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the EMPA-KIDNEY trial. (EMPA-KIDNEY Collaborative Group 2024, PMID 38061371) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
38914124 Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. (Mann 2024, PMID 38914124) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
30697905 SGLT2 inhibitors and cardiovascular, renal and safety outcomes in T2D and CKD: meta-analysis. (Toyama 2019, PMID 30697905) Synthesis; heterogeneity and included-study definitions constrain transport.
36316605 SGLT2 inhibitors in advanced CKD: systematic review and meta-analysis. (Cao 2023, PMID 36316605) Synthesis; heterogeneity and included-study definitions constrain transport.
36927680 Finerenone outcomes in stage 4 CKD and type 2 diabetes. (Sarafidis 2023, PMID 36927680) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
36272755 Executive summary of KDIGO 2022 Diabetes Management in CKD guideline. (Rossing 2022, PMID 36272755) Guideline or commentary; recommendation evidence depends on its review.
33637203 Executive summary of KDIGO 2021 Blood Pressure in CKD guideline. (Cheung 2021, PMID 33637203) Guideline or commentary; recommendation evidence depends on its review.
31533906 Patiromer to enable spironolactone in resistant hypertension and CKD: AMBER. (Agarwal 2019, PMID 31533906) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
40542996 Novel potassium binders, hyperkalemia and RAAS inhibitor optimization: meta-analysis. (Huang 2025, PMID 40542996) Synthesis; heterogeneity and included-study definitions constrain transport.
40470996 Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes (CONFIDENCE). (Agarwal 2025, PMID 40470996) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
42246672 Finerenone in Persons with Chronic Kidney Disease without Diabetes (FIND-CKD). (Heerspink 2026, PMID 42246672) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
41780000 Finerenone in Type 1 Diabetes and Chronic Kidney Disease (FINE-ONE). (Heerspink 2026, PMID 41780000) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
42246414 Finerenone in CKD due to glomerular diseases: prespecified FIND-CKD subgroup analysis. (Neuen 2026, PMID 42246414) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
42567173 Semaglutide kidney outcomes pooled across SELECT, FLOW and SOUL. (Mann 2026, PMID 42567173) Synthesis; heterogeneity and included-study definitions constrain transport.

What can and cannot be concluded

  • Risk associations do not by themselves establish that changing the marker changes risk.
  • A relative effect must be paired with baseline risk, follow-up and the exact endpoint.
  • Albuminuria, acute eGFR change, chronic eGFR slope and kidney failure are not interchangeable.
  • Subgroup consistency is not evidence that every subgroup had adequate power.
  • Guideline recommendations combine evidence with values, feasibility, cost and service capacity.
  • Older adults require competing-mortality and treatment-burden framing.
  • Dialysis and transplantation comparisons are vulnerable to eligibility and immortal-time bias.
  • Modelled lifetime benefit is not a randomized observed benefit.
  • A biochemical response without a patient-important outcome remains a surrogate result.
  • This page is research synthesis, not individualized medical advice.

Research-design checklist

  • Define CKD cause, G category, A category and chronicity at baseline.
  • Report the creatinine or cystatin C equation and laboratory calibration.
  • Prespecify acute and chronic eGFR slopes when haemodynamic effects are expected.
  • Keep sustained GFR decline, kidney failure and replacement therapy separable.
  • Report absolute event risks, follow-up and confidence intervals with relative effects.
  • Treat death as a competing event where it can preclude kidney failure.
  • Measure hyperkalaemia, acute kidney injury and treatment discontinuation consistently.
  • Include symptoms, function, life participation and treatment burden.
  • Describe background RAS, SGLT2, MRA and GLP-1 therapy explicitly.
  • Prespecify albuminuria and cause strata without over-reading underpowered interactions.
  • Record screening, prescribing, persistence and monitoring as separate implementation steps.
  • Report representation, access and affordability variables needed for equity analysis.

Open questions

  • What trial design can test combination and sequence across four classes and still be affordable and powered for kidney failure? CONFIDENCE randomized two classes on albuminuria over 180 days (Agarwal 2025, PMID 40470996); the lifetime four-class estimate is actuarial (Neuen 2024, PMID 37952217). → OQ-1
  • Should implementation and screening trials be required to report treatment initiation and equity, rather than testing yield alone?
  • Which surrogate endpoints have been validated for which disease and drug class? Chronic eGFR slope performed well for SGLT2 inhibitors but proteinuria response failed in FSGS (EMPA-KIDNEY Collaborative Group 2024, PMID 38061371) (Rheault 2023, PMID 37921461). → OQ-19

  • How should registry snapshots be maintained so that a “recruiting” or “no published result” claim does not silently go stale? This audit found FIND-CKD, CONFIDENCE and FINE-ONE published after the page was drafted.

  • Will aldosterone synthase inhibition improve on mineralocorticoid receptor blockade? Explore-CKD gives a four-week blood-pressure and albuminuria signal for lorundrostat (Weir 2026, PMID 42778148); two outcome trials totalling about 13,400 participants on background SGLT2 inhibition: NCT06531824 (closed at 8,371, estimated primary completion 2026-12-31) and NCT06742723 (recruiting, estimated primary completion 2029-12-18). Balcinrenone, a mineralocorticoid receptor modulator, has a 12-week albuminuria signal (Heerspink 2025, PMID 41218621) and a recruiting 2,800-person outcome trial (NCT07624305).

  • Will regulators accept eGFR slope from an adaptive platform trial (NCT06058585) as a basis for approval, or only for prioritisation?
  • Why is no phase 3 trial comparing the established kidney-protective classes head to head on hard endpoints, when combination sequencing is the daily clinical question?

  • Why are kidney transplant recipients still absent from outcome trials when physiology studies show the expected drug effects (PMID 41385300)?

  • Does the iptacopan proteinuria-to-outcome translation in IgA nephropathy generalise to the other mechanisms now in phase 3 with UPCR primary endpoints (NCT06935357, NCT07014826, NCT07390123, NCT06819826, NCT06963827)?

  • Will the ADPKD repurposing trials (metformin NCT04939935, dapagliflozin NCT07280585, hydrochlorothiazide NCT05373264) succeed where novel-mechanism development stalled after tolvaptan? A 50-person empagliflozin feasibility trial found faster total-kidney-volume growth than placebo over 12 months (Seliger 2026, PMID 42925875; NCT05510115).
  • Given the number of agents entering IgA nephropathy simultaneously, what trial design would establish sequencing or combination on clinical outcomes? A 65-person randomized crossover study has compared an endothelin antagonist, an SGLT2 inhibitor and their combination on four-week proteinuria (Chen 2026, PMID 41949916), but the phase 3 programmes remain placebo-controlled and non-comparative.

References

  1. Heerspink et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. PMID 32970396
  2. EMPA-KIDNEY Collaborative Group et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. PMID 36331190
  3. Perkovic et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. PMID 30990260
  4. Bakris et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229. PMID 33264825
  5. Perkovic et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024;391(2):109-121. PMID 38785209
  6. Agarwal et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):474-484. PMID 35023547
  7. Lafayette et al. Targeted-release budesonide in primary IgA nephropathy: NefIgArd 2-year results. Lancet. 2023;402(10405):859-870. PMID 37591292
  8. Rovin et al. Sparsentan versus irbesartan in IgA nephropathy: PROTECT 2-year results. Lancet. 2023;402(10417):2077-2090. PMID 37931634
  9. Rheault et al. Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis. N Engl J Med. 2023;389(26):2436-2445. PMID 37921461
  10. Neuen et al. Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria. Circulation. 2024;149(6):450-462. PMID 37952217
  11. KDIGO CKD Work Group et al. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314. PMID 38490803
  12. Levin et al. Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns. Kidney Int. 2024;105(4):684-701. PMID 38519239
  13. Brenner et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-869. PMID 11565518
  14. Lewis et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860. PMID 11565517
  15. Parving et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870-878. PMID 11565519
  16. Mann et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk: the ONTARGET study. Lancet. 2008;372(9638):547-553. PMID 18707986
  17. Fried et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903. PMID 24206457
  18. Heerspink et al. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(11):743-754. PMID 34619108
  19. EMPA-KIDNEY Collaborative Group et al. Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol. 2024;12(1):39-50. PMID 38061371
  20. Mann et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med. 2024;30(10):2849-2856. PMID 38914124
  21. Toyama et al. SGLT2 inhibitors and cardiovascular, renal and safety outcomes in T2D and CKD: meta-analysis. Diabetes Obes Metab. 2019;21(5):1237-1250. PMID 30697905
  22. Cao H, et al. Effects of sodium-glucose co-transporter-2 inhibitors on kidney, cardiovascular, and safety outcomes in patients with advanced chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol. 2023;60(3):325-335. PMID 36316605
  23. Sarafidis et al. Finerenone outcomes in stage 4 CKD and type 2 diabetes. Clin J Am Soc Nephrol. 2023;18(5):602-612. PMID 36927680
  24. Rossing et al. Executive summary of KDIGO 2022 Diabetes Management in CKD guideline. Kidney Int. 2022;102(5):990-999. PMID 36272755
  25. Cheung et al. Executive summary of KDIGO 2021 Blood Pressure in CKD guideline. Kidney Int. 2021;99(3):559-569. PMID 33637203
  26. Agarwal et al. Patiromer to enable spironolactone in resistant hypertension and CKD: AMBER. Lancet. 2019;394(10208):1540-1550. PMID 31533906
  27. Huang et al. Novel potassium binders, hyperkalemia and RAAS inhibitor optimization: meta-analysis. Drugs. 2025;85(8):1013-1031. PMID 40542996
  28. Agarwal R, et al. Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes. N Engl J Med. 2025;393(6):533-543. PMID 40470996
  29. Heerspink HJL, et al. Finerenone in Persons with Chronic Kidney Disease without Diabetes. N Engl J Med. 2026;395(6):533-545. PMID 42246672
  30. Heerspink HJL, et al. Finerenone in Type 1 Diabetes and Chronic Kidney Disease. N Engl J Med. 2026;394(10):947-957. PMID 41780000
  31. Neuen BL, et al. Finerenone in Patients With Chronic Kidney Disease Due to Glomerular Diseases: A Randomized Clinical Trial. JAMA. 2026;336(3):224-235. PMID 42246414
  32. Mann JFE, et al. Effect of semaglutide on kidney outcomes in the SELECT, FLOW, and SOUL trials: a prespecified pooled analysis. Lancet Diabetes Endocrinol. 2026 Aug 7. PMID 42567173
  33. Heerspink HJL, et al. Atrasentan in patients with IgA nephropathy (ALIGN): final 2.5-year results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2026;407(10546):2387-2401. PMID 42242268
  34. Sridhar VS, et al. Efficacy, Mechanisms, and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Kidney Transplant Recipients: A Randomized, Double-Blind, Placebo-Controlled Trial. Clin J Am Soc Nephrol. 2026;21(4):664-679. PMID 41385300
  35. Anding-Rost K, et al. Exercise during Hemodialysis in Patients with Chronic Kidney Failure. NEJM Evid. 2023;2(9):EVIDoa2300057. PMID 38320198
  36. Barratt J, et al. Iptacopan in IgA Nephropathy - Final 24-Month Data. N Engl J Med. 2026;395(5):465-477. PMID 41910396
  37. David-Neto E, et al. The Effect of Adding Dapagliflozin on Chronic Renal Allograft Dysfunction: A Randomized, Prospective, Double-blind, Placebo-controlled Trial. Transplantation. 2026;110(7):e1527-e1538. PMID 42102257
  38. Kongerud IC, et al. Can sodium-glucose cotransporter 2 (SGLT2) inhibition preserve renal structure and function in de novo kidney transplant recipients? Protocol for a randomised, double-blind, placebo-controlled trial assessing the efficacy of dapagliflozin on kidney structure, function and safety in kidney transplant recipients in Norway-the DEAK study. BMJ Open. 2026;16(6):e117263. PMID 42315275
  39. Chen Q, et al. Endothelin Receptor Antagonist Ambrisentan, Sodium-Glucose Cotransporter 2 Inhibitor Henagliflozin, and Their Combination in IgA Nephropathy: A Randomized Crossover Trial. J Am Soc Nephrol. 2026;37(9):2016-2026. PMID 41949916
  40. Lv J, et al. Telitacicept for IgA Nephropathy - Interim Analysis of a Phase 3 Trial. N Engl J Med. 2026;394:1916-1924. PMID 42127391
  41. Tuttle KR, et al. Effects of semaglutide on kidney disease in type 2 diabetes: a randomized placebo-controlled trial. Nat Med. 2026 Oct 1. PMID 42823485
  42. Weir MR, et al. Results from the Phase 2 Explore-CKD Trial of lorundrostat, a novel aldosterone synthase inhibitor, in participants with uncontrolled hypertension, chronic kidney disease, and albuminuria. Kidney Int. 2026. PMID 42778148
  43. Heerspink HJL, et al. Balcinrenone in combination with dapagliflozin compared with dapagliflozin alone in patients with chronic kidney disease and albuminuria: a randomised, active-controlled double-blind, phase 2b clinical trial. Lancet. 2025;406:2449-2460. PMID 41218621
  44. Heerspink HJL, et al. Initial Changes in eGFR during Treatment with Balcinrenone and Dapagliflozin: An Exploratory Analysis of the MIRO-CKD Trial. Clin J Am Soc Nephrol. 2026 Sep 17. PMID 42752537
  45. Nardone M, et al. A Microsimulation of Eligibility for Cardiorenal Combination Treatment and Potential Deaths Averted. J Am Soc Nephrol. 2026 Oct 9. PMID 42853614
  46. Barratt J, et al. Atacicept in IgA Nephropathy - Phase 3 Trial Final Efficacy Analysis. N Engl J Med. 2026 Oct 22. PMID 42911181
  47. Rizk DV, et al. Sibeprenlimab in IgA Nephropathy - Final Phase 3 Trial Analysis. N Engl J Med. 2026 Oct 22. PMID 42911185
  48. Barratt J, et al. Interim Analysis of a Phase 3 Trial of Povetacicept in IgA Nephropathy. N Engl J Med. 2026 Oct 23. PMID 42912669
  49. Barratt J, et al. Ravulizumab in IgA Nephropathy - Interim Analysis of a Phase 3 Trial. N Engl J Med. 2026 Oct 23. PMID 42912700
  50. Seliger SL, et al. Empagliflozin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Randomized Controlled Trial. J Am Soc Nephrol. 2026 Oct 24. PMID 42925875