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RAS blockade and kidney outcomes

TL;DR — ACE inhibitors and ARBs reduce albuminuria and kidney outcomes in proteinuric CKD, with landmark diabetic-nephropathy evidence from losartan and the IDNT irbesartan trial (Brenner 2001, PMID 11565518) (Lewis 2001, PMID 11565517). More blockade is not better: in ONTARGET (25,620 randomized) combination ramipril plus telmisartan lowered albuminuria more than either agent yet worsened the composite of dialysis, creatinine doubling or death (14.5% vs 13.5% with ramipril; HR 1.09, 95% CI 1.01–1.18) and produced the steepest eGFR decline (−6.11 vs −2.82 mL/min/1.73 m²) (Mann 2008, PMID 18707986). VA NEPHRON-D was stopped early for safety: combination therapy raised hyperkalaemia (6.3 vs 2.6 events per 100 person-years) and acute kidney injury (12.2 vs 6.7 per 100 person-years) with no primary-endpoint benefit (HR 0.88, 95% CI 0.70–1.12) (Fried 2013, PMID 24206457). This page owns kidney endpoints, monitoring and continuation decisions; measurement, targets and general antihypertensive choice remain in the hypertension condition. Modern trials generally add SGLT2 inhibitors and finerenone to tolerated RAS blockade rather than replacing it (Perkovic 2019, PMID 30990260) (Bakris 2020, PMID 33264825).

Kidney endpoint evidence

In RENAAL, losartan added to conventional antihypertensive therapy in 1,513 patients reduced the composite of creatinine doubling, end-stage renal disease or death by 16% (P=0.02) over mean 3.4 years, with creatinine doubling down 25% and ESRD down 28%; the benefit exceeded that attributable to blood-pressure change, and mortality was unaffected (Brenner 2001, PMID 11565518). In IDNT, irbesartan reduced the primary composite risk by 20% versus placebo and 23% versus amlodipine over mean 2.6 years (Lewis 2001, PMID 11565517); IRMA-2 addressed earlier diabetic nephropathy (Parving 2001, PMID 11565519).

Why dual blockade failed

Combining ACE inhibition with ARB therapy lowered albuminuria more but worsened clinically important renal outcomes in ONTARGET and increased hyperkalaemia and acute kidney injury in VA NEPHRON-D (Mann 2008, PMID 18707986) (Fried 2013, PMID 24206457). Surrogate improvement did not rescue harm. Note the division of evidence: ONTARGET reported the harder composite renal outcome, while the hyperkalaemia and AKI rates come from VA NEPHRON-D.

Initial creatinine and potassium changes

RAS blockade changes efferent arteriolar tone; a rise in creatinine requires context, repeat measurement and assessment of volume status, NSAIDs, renal-artery disease and hyperkalaemia.

Continuation architecture

The question is not simply stop/continue. Correct reversible contributors, quantify potassium, reassess dose and use dietary or binder strategies when appropriate (Agarwal 2019, PMID 31533906) (Huang 2025, PMID 40542996).

Layering therapies

CREDENCE, FIDELIO-DKD and FLOW studied treatment largely on background RAS blockade, creating an additive evidence architecture (Perkovic 2019, PMID 30990260) (Bakris 2020, PMID 33264825) (Perkovic 2024, PMID 38785209).

Scope border

Blood-pressure targets are linked rather than reproduced. This page owns albuminuria, eGFR slope and kidney failure; hypertension owns measurement, targets and general drug choice.

Landmark kidney-outcome sequence

Trial Comparison Kidney reading
IDNT Irbesartan vs amlodipine/placebo Primary composite risk 20% lower vs placebo and 23% lower vs amlodipine (Lewis 2001, PMID 11565517)
RENAAL Losartan vs placebo on conventional therapy (n=1,513) Composite risk 16% lower; creatinine doubling −25%, ESRD −28%; no mortality effect (Brenner 2001, PMID 11565518)
IRMA-2 Irbesartan in earlier diabetic nephropathy Albuminuria-stage evidence, not the IDNT hard-outcome population (Parving 2001, PMID 11565519)
ONTARGET Ramipril, telmisartan or both (n=25,620) Composite dialysis/creatinine-doubling/death 14.5% vs 13.5%; HR 1.09 (1.01–1.18) despite greater albuminuria lowering (Mann 2008, PMID 18707986)
VA NEPHRON-D Losartan + lisinopril vs losartan (n=1,448) Stopped early: hyperkalaemia 6.3 vs 2.6 and AKI 12.2 vs 6.7 per 100 person-years; primary HR 0.88 (0.70–1.12) (Fried 2013, PMID 24206457)
AMBER Patiromer vs placebo with spironolactone Tests potassium enablement, not kidney failure (Agarwal 2019, PMID 31533906)

The non-diabetic evidence base

The 2001 ARB trials established RAS blockade in type 2 diabetic nephropathy, but the non-diabetic case was made earlier and separately. REIN randomized 352 patients with chronic non-diabetic proteinuric nephropathy to ramipril or placebo on top of conventional therapy targeted to the same diastolic blood pressure below 90 mmHg — the design feature that makes it interpretable. In the stratum with proteinuria ≥3 g/24 h, the trial was stopped early: GFR decline was 0.53 ± 0.08 mL/min per month with ramipril versus 0.88 ± 0.13 with placebo (p = 0.03), and the percentage reduction in proteinuria was inversely correlated with GFR decline and predicted the reduction in risk of doubling of creatinine (GISEN Group 1997, PMID 9217756). The proteinuria–outcome correlation within the treated arm is the origin of the modern surrogate argument.

The follow-up study added a finding that changes how the drug should be thought of. Among 97 patients continuing or switching to ramipril, mean monthly GFR decline fell from 0.44 ± 0.54 to 0.10 ± 0.50 mL/min/1.73 m² in those originally randomized to ramipril (p = 0.017) and from 0.81 ± 1.12 to 0.14 ± 0.87 in those switched from placebo (p = 0.017); at final visit mean GFR was 12 mL/min/1.73 m² higher (33% better) in the originally-ramipril group (35.5 ± 19.0 vs 23.8 ± 9.4, p = 0.01), and 19 versus 35 patients progressed to end-stage renal failure (p = 0.027) (Ruggenenti 1998, PMID 9788454). Late starters benefited, but the ground lost during the placebo period was not recovered — a within-trial demonstration of why delay is not neutral.

Advanced CKD: two trials, opposite designs, compatible answers

Starting late still works. Among 224 patients without diabetes and serum creatinine 3.1–5.0 mg/dL randomized to benazepril 20 mg/day or placebo on top of conventional antihypertensives and followed a mean 3.4 years, the composite of doubled creatinine, ESRD or death occurred in 41% versus 60% — a 43% relative risk reduction (p = 0.005) — with a 52% reduction in proteinuria and a 23% reduction in the rate of renal function decline, and this was not attributable to blood-pressure control. Major adverse events were similar between arms (Hou 2006, PMID 16407508). This is the strongest randomized evidence that ACE inhibition retains efficacy at creatinine levels where many clinicians stop.

Stopping late does not help. STOP-ACEi randomized 411 patients with eGFR below 30 and progressive CKD to discontinue or continue RAS inhibitors. At 3 years, least-squares mean eGFR was 12.6 ± 0.7 in the discontinuation group and 13.3 ± 0.6 mL/min/1.73 m² in the continuation group (difference −0.7; 95% CI −2.5 to 1.0; p = 0.42), with no heterogeneity across prespecified subgroups. ESKD or initiation of renal replacement therapy occurred in 128 (62%) versus 115 (56%) — HR 1.28 (95% CI 0.99–1.65) — and adverse events were similar (Bhandari 2022, PMID 36326117). The trial was designed to test the hypothesis that withdrawal raises eGFR in advanced CKD; it found no such benefit, and the confidence interval on kidney failure leans toward harm from stopping without excluding no difference.

Taken together the two trials support continuing RAS blockade into advanced CKD in the absence of a specific reason to stop, while noting that STOP-ACEi was open-label, that its primary endpoint was an eGFR level rather than an event, and that 411 patients cannot resolve a hazard ratio whose interval spans 0.99–1.65.

Blood pressure target: the kidney answer differs from the cardiovascular answer

In SPRINT's prespecified CKD subgroup (n = 1,330 intensive, 1,316 standard, median 3.3 years), targeting systolic BP below 120 rather than below 140 mmHg gave a primary cardiovascular composite HR of 0.81 (95% CI 0.63–1.05) and all-cause death HR 0.72 (0.53–0.99), with no interaction by CKD status (p ≥ 0.30). The prespecified kidney outcome — ≥50% eGFR decline or ESRD — occurred in 15 versus 16 participants (HR 0.90, 95% CI 0.44–1.83), and after the first 6 months the intensive group had a slightly faster eGFR slope (−0.47 vs −0.32 mL/min/1.73 m²/year, p < 0.03) (Cheung 2017, PMID 28642330). Intensive control therefore bought mortality benefit at the cost of a marginally steeper eGFR slope and with kidney event counts far too small to inform anything.

Pooling individual patient data from AASK, ACCORD, MDRD and SPRINT (4,983 hypertensive CKD patients; achieved 125.0 vs 136.9 mmHg), all-cause mortality with a target below 130 versus below 140 mmHg gave HR 0.87 (0.69–1.08; p = 0.21) overall, reaching HR 0.79 (0.63–1.00; p = 0.048) after excluding participants with GFR ≥60 and those under intensive glycaemic control (Aggarwal 2019, PMID 31067189). A post hoc SPRINT/ACCORD-BP analysis of 10,946 participants found renal failure reduced by intensive control in those with baseline CKD (HR 0.46, 95% CI 0.22–0.97) and not in those without (HR 0.88, 0.52–1.49; p-interaction 0.128), while the risk of a ≥30% eGFR reduction rose and albuminuria fell in both groups; intensive control increased progression to moderate- or high-risk KDIGO categories but not to very-high risk (Xu 2025, PMID 41117098).

This is a genuine and unresolved tension: the same intervention lowers albuminuria and mortality while producing more eGFR-defined "progression". Whether the extra eGFR decline is haemodynamic and benign — the same interpretive problem as the SGLT2 dip — or represents real nephron loss has not been settled by any trial designed to answer it.

Trial / analysis Population Kidney result Mortality/CV result
REIN (PMID 9217756) Non-diabetic, proteinuria ≥3 g/24 h, n=352 GFR decline 0.53 vs 0.88 mL/min/month (p=0.03) Not powered
REIN follow-up (PMID 9788454) 97 continuing/crossing over Final GFR 35.5 vs 23.8 mL/min/1.73 m² (p=0.01); ESRF 19 vs 35 (p=0.027) —
Hou benazepril (PMID 16407508) Non-diabetic, creatinine 3.1–5.0 mg/dL, n=224 Composite 41% vs 60%; 43% RRR (p=0.005) Included in composite
STOP-ACEi (PMID 36326117) eGFR <30, progressive, n=411 eGFR difference −0.7 (−2.5 to 1.0); ESKD/KRT HR 1.28 (0.99–1.65) No difference
SPRINT CKD subgroup (PMID 28642330) CKD, non-diabetic, n=2,646 ≥50% eGFR decline/ESRD HR 0.90 (0.44–1.83); slope −0.47 vs −0.32/yr Death HR 0.72 (0.53–0.99)
Pooled AASK/ACCORD/MDRD/SPRINT (PMID 31067189) CKD + hypertension, n=4,983 Not primary Death HR 0.87 (0.69–1.08); 0.79 (0.63–1.00) in G3+ subset

What combining layers is worth, in years

Expressing benefit as event-free time makes the stacking question concrete. Combining trial-level effects of ACE inhibitor/ARB therapy (ramipril/benazepril, n=690) with those of dapagliflozin (n=1,398) gives an aggregate HR of 0.35 (95% CI 0.30–0.41) versus no treatment for the composite of doubled creatinine, kidney failure or death, projected onto the 697 DAPA-CKD participants with albuminuric CKD without diabetes (Vart 2022, PMID 36414316). This is a projection built by multiplying independently estimated effects, not an observed randomized comparison — the same caveat that applies to every lifetime-benefit estimate on the therapy pages, and the reason CONFIDENCE (PMID 40470996) matters as the only trial to have randomized two of these layers head to head.

Blood-pressure lowering works at every CKD stage — with one caveat

The concern that antihypertensive treatment might be less beneficial or less safe in advanced CKD has now been answered by an individual-participant meta-analysis of the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. From 52 randomized trials (363,684 participants), 285,124 participants from 46 trials met eligibility (40.7% women; 20.7% with CKD at baseline; 30.2% with type 2 diabetes), followed a median 4.4 years (IQR 3.2–5.1). A 5 mmHg reduction in systolic blood pressure reduced major cardiovascular disease — fatal or non-fatal stroke, ischaemic heart disease, or heart-failure hospitalisation or death — by essentially the same amount with CKD (HR 0.91, 95% CI 0.87–0.94) and without it (HR 0.90, 0.88–0.93; p-interaction > 0.99). The relative effect was consistent across all CKD stages including 4–5 (p-interaction > 0.99), across proteinuria status, and across baseline blood-pressure categories down to below 120/70 mmHg, with class-specific effects unchanged across subgroups (Zeng 2026, PMID 42035778).

The caveat is diabetes. Among participants with CKD, the relative benefit was markedly attenuated in those who also had diabetes (HR 0.96, 95% CI 0.90–1.02) compared with those who did not (0.88, 0.84–0.93; p-interaction = 0.044) (Zeng 2026, PMID 42035778). This is a subgroup interaction in a very large dataset and it runs against the intuition that higher-risk patients gain more; it has no accepted mechanistic explanation and should be treated as a finding to be replicated rather than acted on.

Reaching the target in advanced CKD: thiazides work after all

Thiazide diuretics are widely believed to lose efficacy below an eGFR of about 30. CLICK randomized 160 patients with stage 4 CKD and poorly controlled hypertension confirmed on 24-hour ambulatory monitoring (mean eGFR 23.2 ± 4.2 mL/min/1.73 m², 76% with diabetes, 60% already on loop diuretics, mean 3.4 ± 1.4 antihypertensive drugs) to chlorthalidone 12.5 mg daily titrated to a maximum of 50 mg, or placebo, stratified by prior loop-diuretic use. The adjusted change in 24-hour ambulatory systolic blood pressure at 12 weeks was −11.0 mmHg (95% CI −13.9 to −8.1) with chlorthalidone versus −0.5 mmHg (−3.5 to 2.5) with placebo — a between-group difference of −10.5 mmHg (95% CI −14.6 to −6.4; p < 0.001) (Agarwal 2021, PMID 34739197).

An 10.5 mmHg ambulatory systolic difference in an already heavily treated stage-4 population is a large effect, and it directly contradicts the clinical folklore. Set against the Zeng result that each 5 mmHg is worth an 9–10% relative cardiovascular risk reduction at every CKD stage, the two findings together make the case that resistant hypertension in advanced CKD is an under-treated rather than untreatable problem — although CLICK's 12-week endpoint was blood pressure, not events, and its 160 patients cannot address safety over years.

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
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.
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.
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.
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.
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.
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.
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.
32970396 Dapagliflozin in Patients with Chronic Kidney Disease. (Heerspink 2020, PMID 32970396) 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.
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.
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.
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.
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.
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.
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.
32061315 Global, regional, and national burden of chronic kidney disease, 1990-2017. (GBD CKD Collaboration 2020, PMID 32061315) Modelled projection; the estimate follows from the model inputs and assumptions, not from observed randomized follow-up.
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.

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 is the right response to a creatinine rise after starting RAS blockade — continue, reduce, or stop — and does the choice change kidney outcomes? Practice rests on physiology and observational data, not randomisation.
  • Does potassium-binder enablement of RAS blockade preserve the cardiorenal benefit that continuation is meant to protect? AMBER established 12-week persistence, not outcomes (Agarwal 2019, PMID 31533906) (Huang 2025, PMID 40542996). → OQ-6
  • Should RAS blockade be continued or withdrawn in advanced CKD approaching kidney failure? Neither ONTARGET nor VA NEPHRON-D addresses withdrawal (Mann 2008, PMID 18707986) (Fried 2013, PMID 24206457).

  • Now that finerenone, SGLT2 inhibitors and semaglutide all sit on top of RAS blockade, is maximal RAS dose still the right foundation, or would a lower dose with more layers do better (Agarwal 2025, PMID 40470996)?

  • Is the extra eGFR decline produced by intensive blood-pressure control haemodynamic and benign, or real nephron loss? Intensive control simultaneously lowers albuminuria and mortality while increasing ≥30% eGFR reduction and KDIGO category progression (Cheung 2017, PMID 28642330) (Xu 2025, PMID 41117098).

  • Does stopping RAS blockade in advanced CKD harm? STOP-ACEi found no eGFR benefit from withdrawal and a kidney-failure hazard ratio of 1.28 (0.99–1.65) that neither excludes harm nor establishes it (Bhandari 2022, PMID 36326117).
  • Why did late-started ramipril slow decline without recovering GFR already lost during placebo exposure, and does the same asymmetry apply to SGLT2 inhibitors (Ruggenenti 1998, PMID 9788454)?

  • Is the projected combination hazard ratio of 0.35 (0.30–0.41) for RAS plus SGLT2 inhibition in non-diabetic albuminuric CKD achievable in practice, given that it was derived by multiplying separately estimated trial effects (Vart 2022, PMID 36414316)?

  • Why is the cardiovascular benefit of blood-pressure lowering attenuated in people who have both CKD and diabetes (HR 0.96, 0.90–1.02) compared with CKD alone (0.88, 0.84–0.93; p-interaction 0.044) (Zeng 2026, PMID 42035778)? No mechanism has been proposed and the interaction needs replication.

  • Does the 10.5 mmHg ambulatory systolic reduction from chlorthalidone in stage 4 CKD (Agarwal 2021, PMID 34739197) translate into events, and what is its long-term safety at an eGFR near 23 mL/min/1.73 m²?

References

  1. 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
  2. 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
  3. 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
  4. Fried et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903. PMID 24206457
  5. Perkovic et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. PMID 30990260
  6. 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
  7. 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
  8. Agarwal et al. Patiromer to enable spironolactone in resistant hypertension and CKD: AMBER. Lancet. 2019;394(10208):1540-1550. PMID 31533906
  9. Huang et al. Novel potassium binders, hyperkalemia and RAAS inhibitor optimization: meta-analysis. Drugs. 2025;85(8):1013-1031. PMID 40542996
  10. 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
  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. Heerspink et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. PMID 32970396
  14. 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
  15. EMPA-KIDNEY Collaborative Group et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. PMID 36331190
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. Rossing et al. Executive summary of KDIGO 2022 Diabetes Management in CKD guideline. Kidney Int. 2022;102(5):990-999. PMID 36272755
  24. Cheung et al. Executive summary of KDIGO 2021 Blood Pressure in CKD guideline. Kidney Int. 2021;99(3):559-569. PMID 33637203
  25. GBD CKD Collaboration et al. Global, regional, and national burden of chronic kidney disease, 1990-2017. Lancet. 2020;395(10225):709-733. PMID 32061315
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