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Inherited and glomerular disease

TL;DR — Cause-specific CKD therapy is arriving unevenly. Tolvaptan slowed total-kidney-volume growth and eGFR decline in selected ADPKD populations but causes aquaresis and requires liver-safety monitoring (Torres 2012, PMID 23121377) (Torres 2017, PMID 29105594). In IgA nephropathy, targeted-release budesonide and sparsentan improved kidney endpoints relative to control in phase 3 programs (Lafayette 2023, PMID 37591292) (Rovin 2023, PMID 37931634). In FSGS, sparsentan improved partial proteinuria remission but not 108-week eGFR slope, a direct warning against equating surrogate response with preserved function (Rheault 2023, PMID 37921461). Genomics can replace an imprecise histologic label with a causal diagnosis in selected patients, though an unselected biopsy cohort yielded a molecular diagnosis in only 4% (2 of 50) (Benson 2020, PMID 32723786).

ADPKD

TEMPO 3:4 reduced annual total-kidney-volume growth from 5.5% to 2.8% and slowed kidney-function decline, with more discontinuation for aquaretic and liver-related effects (Torres 2012, PMID 23121377). REPRISE extended eGFR evidence to later-stage disease (Torres 2017, PMID 29105594).

IgA nephropathy

NefIgArd reported a 5.05 mL/min/1.73 m² two-year time-weighted eGFR difference favouring targeted-release budesonide (Lafayette 2023, PMID 37591292). PROTECT showed sparsentan benefit versus irbesartan over two years (Rovin 2023, PMID 37931634).

FSGS

DUPLEX proteinuria remission was 42% versus 26% at week 36, but total eGFR-slope difference was 0.3 (95% CI −1.7 to 2.4) mL/min/1.73 m²/year (Rheault 2023, PMID 37921461).

Genomic diagnosis

Testing is most useful when phenotype, family history or biopsy suggests monogenic disease: yield fell to 4% (2 of 50) when a 227-gene panel was applied to unscreened biopsy referrals, against up to 18% in cohorts pre-selected for suspected genetic aetiology, and the authors' own conclusion was that panels should follow suspicion rather than replace it (Benson 2020, PMID 32723786). Adult-onset monogenic disease is nonetheless missed when family history is not taken (Granhoj 2022, PMID 34515170). Diagnostic yield and management impact must both be reported.

Shared supportive platform

Cause-specific therapy sits on albuminuria reduction, cardiovascular prevention and CKD-complication management; it does not erase supportive care.

Border

Detailed immunosuppression protocols and disease-by-disease pathology taxonomies remain outside this overview page.

Cause-specific outcome table

Disease / trial Intervention Quantitative result Caution
ADPKD / TEMPO 3:4 Tolvaptan Kidney-volume growth 2.8% vs 5.5%/year Selected rapidly progressive population; aquaresis/liver monitoring (Torres 2012, PMID 23121377)
Later ADPKD / REPRISE Tolvaptan One-year eGFR decline −2.34 vs −3.61 mL/min/1.73 m² Shorter horizon; discontinuation after run-in (Torres 2017, PMID 29105594)
IgA / NefIgArd Targeted-release budesonide Two-year time-weighted eGFR difference +5.05 (3.24–7.38) Steroid-class adverse effects occurred (Lafayette 2023, PMID 37591292)
IgA / PROTECT Sparsentan vs irbesartan Chronic slope difference +1.1 (0.1–2.1) mL/min/1.73 m²/year Total-slope CI crossed zero (Rovin 2023, PMID 37931634)
FSGS / DUPLEX Sparsentan vs irbesartan Proteinuria remission 42% vs 26%; slope difference +0.3 (−1.7 to 2.4) Surrogate improved, primary eGFR endpoint did not (Rheault 2023, PMID 37921461)

ADPKD: the one inherited kidney disease with a licensed disease-modifying drug

Early disease. TEMPO 3:4 randomized 1,445 patients aged 18–50 with total kidney volume ≥750 mL and estimated creatinine clearance ≥60 mL/min (2:1) to tolvaptan or placebo for three years. Total kidney volume increased 2.8%/year (95% CI 2.5–3.1) with tolvaptan versus 5.5%/year (5.1–6.0) with placebo (p < 0.001). The composite of clinical progression favoured tolvaptan (44 versus 50 events per 100 follow-up-years, p = 0.01), driven by worsening kidney function (2 versus 5 per 100 person-years, p < 0.001) and kidney pain (5 versus 7, p = 0.007), and the reciprocal-creatinine slope was slower (−2.61 versus −3.81 per year; p < 0.001). Aquaretic and hepatic adverse events drove discontinuation to 23% versus 14% (Torres 2012, PMID 23121377).

Later disease. REPRISE used a randomized-withdrawal design after an 8-week sequential placebo and tolvaptan run-in that screened out patients unable to tolerate the drug, then randomized 1,370 patients (aged 18–55 with eGFR 25–65, or 56–65 with eGFR 25–44) 1:1 for 12 months. eGFR change from baseline was −2.34 (95% CI −2.81 to −1.87) with tolvaptan versus −3.61 (−4.08 to −3.14) mL/min/1.73 m² with placebo — a difference of 1.27 (0.86–1.68; p < 0.001). ALT rose above three times the upper limit of normal in 38/681 (5.6%) on tolvaptan versus 8/685 (1.2%) on placebo, reversibly on stopping (Torres 2017, PMID 29105594).

The two trials together support treatment across a wide eGFR range, but both carry the same interpretive load: the benefit is roughly 1 mL/min/1.73 m²/year, the aquaresis is lifelong and burdensome, and REPRISE's run-in means the randomized population had already proved it could tolerate the drug — so real-world tolerability is worse than the trial's discontinuation figures suggest.

Endothelin–angiotensin dual blockade in glomerular disease

IgA nephropathy. Sparsentan reduced proteinuria versus irbesartan in PROTECT (Rovin 2023, PMID 37931634), the trial that established dual endothelin–angiotensin receptor blockade in IgA nephropathy alongside targeted-release budesonide (Lafayette 2023, PMID 37591292).

FSGS: the same drug, a different answer. DUPLEX randomized 371 patients aged 8–75 with primary FSGS to sparsentan or irbesartan for 108 weeks. The 36-week surrogate endpoint was met: partial remission of proteinuria (uPCR ≤1.5 g/g and >40% reduction from baseline) in 42.0% versus 26.0% (p = 0.009), sustained through 108 weeks. The primary endpoint was not: the between-group difference in total eGFR slope from day 1 to week 108 was 0.3 mL/min/1.73 m²/year (95% CI −1.7 to 2.4) and in chronic slope from week 6 to week 108 was 0.9 (−1.3 to 3.0) (Rheault 2023, PMID 37921461).

This is the cleanest available demonstration of the surrogate problem in glomerular disease. A drug that produced a large, sustained and statistically robust proteinuria response over two years produced no detectable difference in eGFR slope in the same trial and the same patients. It is a direct counterexample to the general albuminuria-surrogate result (see definition, staging and measurement), and it means the ~19% hazard reduction per 30% uACR reduction estimated across 48 trials (PMID 41198855) cannot be applied to an individual disease without checking.

Membranous nephropathy: mechanism-directed therapy with a durability advantage

MENTOR randomized 130 patients with membranous nephropathy, proteinuria ≥5 g/24 h and creatinine clearance ≥40 mL/min/1.73 m², all on at least three months of angiotensin blockade, to intravenous rituximab (two 1,000 mg infusions 14 days apart, repeated at 6 months for partial response) or oral cyclosporine (3.5 mg/kg/day for 12 months), following them 24 months. At 12 months, complete or partial remission occurred in 39/65 (60%) versus 34/65 (52%) — risk difference 8 percentage points (95% CI −9 to 25; p = 0.004 for non-inferiority. At 24 months the gap opened decisively: 39 (60%) versus 13 (20%), risk difference 40 percentage points (25–55; p < 0.001 for both non-inferiority and superiority). Among patients in remission who were anti-PLA2R positive, autoantibody decline was faster, larger and more durable with rituximab, and serious adverse events were numerically fewer (11 [17%] versus 20 [31%]; p = 0.06) (Fervenza 2019, PMID 31269364).

The 12-month equivalence and 24-month superiority pattern is the point: cyclosporine induces remission and loses it on withdrawal, while B-cell depletion removes the antibody-producing clone. It is also the clearest case in glomerular disease where an autoantibody titre functions as a mechanistic readout rather than a correlate.

Disease Intervention Result What it establishes
ADPKD, eGFR ≥60 equivalent Tolvaptan (TEMPO 3:4, n=1,445) TKV growth 2.8 vs 5.5%/yr; 1/creatinine slope −2.61 vs −3.81/yr (PMID 23121377) Structural and functional slowing; 23% discontinuation
ADPKD, eGFR 25–65 Tolvaptan (REPRISE, n=1,370) eGFR −2.34 vs −3.61 mL/min/1.73 m² over 1 yr (difference 1.27, 0.86–1.68) (PMID 29105594) Benefit persists in later disease; ALT >3× ULN in 5.6%
IgA nephropathy Sparsentan vs irbesartan (PROTECT) Proteinuria reduction (PMID 37931634) Dual receptor blockade in IgAN
Primary FSGS Sparsentan vs irbesartan (DUPLEX, n=371) Partial remission 42.0% vs 26.0% (p=0.009); total eGFR slope difference 0.3 (−1.7 to 2.4) (PMID 37921461) Proteinuria response without slope benefit
Membranous nephropathy Rituximab vs cyclosporine (MENTOR, n=130) Remission 60% vs 52% at 12 mo; 60% vs 20% at 24 mo (PMID 31269364) Durability, not induction rate, distinguishes them

IgA nephropathy has become the fastest-moving field in nephrology

By 2023, IgA nephropathy had entered a period of rapid disease-specific drug development; by 2026 several mechanistically distinct agents had randomized evidence, making it a useful worked example of surrogate-to-outcome translation in glomerular disease.

Gut-directed immunosuppression. NefIgArd randomized 364 adults with primary IgA nephropathy, eGFR 35–90 and persistent proteinuria (uPCR ≥0.8 g/g or ≥1 g/24 h) despite optimised RAS blockade, at 132 sites in 20 countries, to targeted-release budesonide (Nefecon) 16 mg/day or placebo for 9 months followed by 15 months off drug, with time-weighted average eGFR over 2 years as the primary endpoint (Lafayette 2023, PMID 37591292). The design detail that matters is the 15-month off-treatment observation: a 9-month treatment whose effect is judged 15 months after it stops is a much harder test than an on-treatment comparison.

Alternative complement pathway inhibition — proteinuria, then function. APPLAUSE-IgAN randomized adults with biopsy-confirmed IgA nephropathy and 24-hour uPCR ≥1 g/g despite optimised supportive therapy 1:1 to oral iptacopan 200 mg twice daily or placebo for 24 months (222 and 221 in the main population). The prespecified 9-month interim analysis in the first 250 randomized patients found the adjusted geometric mean 24-hour uPCR 38.3% lower with iptacopan (95% CI 26.0–48.6) (Perkovic 2025, PMID 39453772).

The final 24-month analysis converted that surrogate into function and events. Among 477 patients (238 iptacopan, 239 placebo), the annualized total eGFR slope was −3.10 mL/min/1.73 m²/year with iptacopan versus −6.12 with placebo — a difference of 3.02 (95% CI 2.02–4.01; adjusted p < 0.001) — and the composite kidney-failure endpoint (sustained ≥30% eGFR decline, sustained eGFR <15, maintenance dialysis, transplant, or kidney-failure death) occurred in 21.4% versus 33.5% (HR 0.57, 95% CI 0.40–0.81; adjusted p = 0.003) (Barratt 2026, PMID 41910396).

This is the result that matters most for the surrogate debate on this page. A 38.3% proteinuria reduction at 9 months was followed by a halving of the eGFR slope and a 43% relative reduction in a hard kidney-failure composite in the same trial — the direct counterpart to the FSGS case above, where a comparable proteinuria response produced no slope difference at all. Whether proteinuria is a valid surrogate is therefore not a property of proteinuria; it is a property of the disease and the mechanism being modulated.

C5 inhibition. A phase 2 trial randomized 66 adults with IgA nephropathy, proteinuria ≥1 g/day and eGFR ≥30 on stable RAS blockade 2:1 to intravenous ravulizumab every 8 weeks or placebo for 26 weeks, followed by open-label ravulizumab to week 50. Urine protein fell 41.9% (95% CI −50.2 to −32.0) with ravulizumab versus 16.8% (−31.8 to +1.6) with placebo — a 30.1% treatment effect (p = 0.005) — with −44.8% (−55.1 to −32.1) at week 50 and −45.1% in placebo patients crossed over at week 26 (Lafayette 2025, PMID 39455063).

Two complement inhibitors acting at different points of the cascade — factor B upstream, C5 downstream — both reduce proteinuria by comparable amounts. Only the factor B inhibitor has been tested to a kidney-failure endpoint.

A first randomized combination comparison. A 65-person open-label crossover trial compared four weeks each of ambrisentan, henagliflozin and their combination. Proteinuria fell 44% with combination, similar to 48% with ambrisentan and more than 21% with henagliflozin; combination caused less fluid retention than ambrisentan alone. The short treatment periods and surrogate endpoint do not establish sequence or clinical-outcome benefit (Chen 2026, PMID 41949916).

Agent Mechanism Design Key result
Nefecon (PMID 37591292) Gut mucosal targeted-release budesonide 364 patients, 9 months treatment + 15 months off-drug Primary endpoint: 2-year time-weighted average eGFR
Sparsentan (PMID 37931634) Dual endothelin A / angiotensin II receptor antagonist vs irbesartan, active control Proteinuria reduction
Atrasentan (PMID 42242268) Selective endothelin A antagonist 404 patients, 132 weeks eGFR difference 2.4 (−0.1 to 4.8) at week 136; slope difference 1.4/yr (0.5–2.3)
Iptacopan (PMIDs: 39453772, 41910396) Complement factor B, alternative pathway 477 patients, 24 months uPCR −38.3% at 9 months; slope −3.10 vs −6.12/yr; kidney-failure composite HR 0.57 (0.40–0.81)
Ravulizumab (PMID 39455063) Terminal complement C5 Phase 2, 66 patients, 26 weeks + crossover Proteinuria treatment effect 30.1% (p=0.005)

Immune-mediated kidney disease: three trials that changed standard care

Lupus nephritis — calcineurin inhibition. AURORA 1 randomized 357 patients with biopsy-proven class III, IV or V lupus nephritis at 142 sites in 27 countries to voclosporin 23.7 mg twice daily or placebo, both on background mycophenolate mofetil 1 g twice daily with rapidly tapered low-dose oral steroids. The 52-week primary endpoint — a composite complete renal response requiring uPCR ≤0.5 mg/mg, stable kidney function (eGFR ≥60 or no confirmed fall >20% from baseline), no rescue medication and no more than 10 mg prednisone-equivalent daily during weeks 44–52 — was reached by 41% (73/179) on voclosporin versus 23% (40/178) on placebo (OR 2.65, 95% CI 1.64–4.27; Rovin 2021, PMID 33971155). The composite endpoint is unusually strict: it requires a proteinuria target and function stability and steroid withdrawal simultaneously, so its response rate is not comparable to single-component response rates in older trials.

Lupus nephritis — B-cell activating factor inhibition, with a phenotype boundary. Post-hoc analysis of BLISS-LN (448 patients randomized to belimumab 10 mg/kg intravenously or placebo with standard therapy over 104 weeks) found belimumab most effective for the primary and complete kidney responses in patients with proliferative lupus nephritis and a baseline uPCR below 3 g/g, with no observed improvement in patients with sub-epithelial deposits or baseline uPCR of 3 g/g or above. Across the whole population, belimumab reduced the risk of kidney-related events or death and of lupus nephritis flare, reduced the risk of a sustained 30% or 40% eGFR decline versus standard therapy alone, and attenuated the annual rate of eGFR decline among those remaining on study (Rovin 2022, PMID 34560137). The histological and proteinuria boundaries are the useful content: this is one of the few glomerular-disease datasets in which a treatment effect is explicitly located within a phenotype rather than assumed to be uniform.

ANCA-associated vasculitis — complement C5a receptor blockade. Post-hoc analysis of the ADVOCATE trial restricted to the 268 of 330 patients (81.2%) with kidney involvement compared an avacopan regimen with a prednisone taper. Remission at week 26 was 73.9% (99/134) versus 70.9% (95/134) and sustained remission at week 52 was 67.9% (91/134) versus 56.7% (76/134); relapse after remission was 9.4% versus 20.9% (HR 0.43, 95% CI 0.22–0.85). Recovery of kidney function, speed of albuminuria and haematuria reduction, and glucocorticoid toxicity index all favoured avacopan, with no new safety signals (Geetha 2025, PMID 40814647).

The avacopan result is a different kind of advance from the others: remission rates at 26 weeks were similar, and the benefit lies in relapse prevention, faster kidney recovery and — most consequentially for long-term outcome — reduced glucocorticoid exposure. A therapy whose primary value is steroid replacement rather than superior remission induction requires a different evidentiary framing, and the glucocorticoid toxicity index is the instrument doing that work.

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
23121377 Tolvaptan in patients with autosomal dominant polycystic kidney disease. (Torres 2012, PMID 23121377) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
29105594 Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. (Torres 2017, PMID 29105594) 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.
32723786 Diagnostic utility of genetic testing in patients undergoing renal biopsy. (Benson 2020, PMID 32723786) Observational or conceptual evidence; association is not treatment effect.
34515170 Family History is Important to Identify Patients with Monogenic Causes of Adult-Onset CKD. (Granhoj 2022, PMID 34515170) Observational or conceptual evidence; association is not treatment effect.
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.
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.
22038337 A population-based approach for the definition of chronic kidney disease: CKD Prognosis Consortium. (Cirillo 2012, PMID 22038337) Synthesis; heterogeneity and included-study definitions constrain transport.
23243116 Cohort profile: the chronic kidney disease prognosis consortium. (Matsushita 2013, PMID 23243116) Observational or conceptual evidence; association is not treatment effect.
37787795 Estimated GFR, Albuminuria, and Adverse Outcomes: individual-participant data meta-analysis. (CKD Prognosis Consortium 2023, PMID 37787795) Synthesis; heterogeneity and included-study definitions constrain transport.
30348535 Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities. (Inker 2019, PMID 30348535) Synthesis; heterogeneity and included-study definitions constrain transport.
34554658 New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. (Inker 2021, PMID 34554658) Observational or conceptual evidence; association is not treatment effect.
25399733 Blood pressure in early autosomal dominant polycystic kidney disease. (Schrier 2014, PMID 25399733) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
34746741 Genomics Integration Into Nephrology Practice. (Pinto E Vairo 2021, PMID 34746741) Observational or conceptual evidence; association is not treatment effect.
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.
36272755 Executive summary of KDIGO 2022 Diabetes Management in CKD guideline. (Rossing 2022, PMID 36272755) Guideline or commentary; recommendation evidence depends on its review.
26757465 Multinational assessment of equations predicting kidney failure. (Tangri 2016, PMID 26757465) Synthesis; heterogeneity and included-study definitions constrain transport.
34563581 A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. (Delgado 2022, PMID 34563581) Guideline or commentary; recommendation evidence depends on its review.
36857500 Kidney Failure Risk Equation evaluation with novel inputs in 59 cohorts. (Grams 2023, PMID 36857500) Observational or conceptual evidence; association is not treatment effect.
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.

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

  • Which IgA-nephropathy sequence best converts a proteinuria response into preserved GFR? NefIgArd and PROTECT report two-year data on different endpoints, and the FSGS result shows the conversion is not automatic (Lafayette 2023, PMID 37591292) (Rovin 2023, PMID 37931634) (Rheault 2023, PMID 37921461). → OQ-9
  • Does finerenone belong in the glomerular-disease platform? A prespecified FIND-CKD subgroup of 903 participants (46% IgA nephropathy, 24% FSGS) was exploratory, not a powered trial in these diseases (Neuen 2026, PMID 42246414).
  • Which ADPKD patients gain enough from tolvaptan to accept aquaresis and liver monitoring? TEMPO 3:4 selected a rapidly progressive population and REPRISE ran one year (Torres 2012, PMID 23121377) (Torres 2017, PMID 29105594).

  • Would a prospective genotype-to-treatment study show that a molecular diagnosis changes management often enough to justify broad panels (Benson 2020, PMID 32723786)? → OQ-17

  • Why did sparsentan produce a large sustained proteinuria response in FSGS with no eGFR slope difference (0.3 mL/min/1.73 m²/yr, −1.7 to 2.4) (Rheault 2023, PMID 37921461) when the same class works in IgA nephropathy? Either FSGS proteinuria is a weaker surrogate, or the trial was underpowered for slope.

  • What is real-world tolerability of tolvaptan? REPRISE randomized only patients who had already tolerated a run-in (Torres 2017, PMID 29105594) and TEMPO 3:4 discontinuation was 23% versus 14% (Torres 2012, PMID 23121377).

  • Can anti-PLA2R titre serve as a treat-to-target endpoint in membranous nephropathy, given that its decline was faster, larger and more durable with rituximab than cyclosporine among patients in remission (Fervenza 2019, PMID 31269364)?

  • Why does proteinuria predict eGFR slope in IgA nephropathy — a 38.3% reduction preceding a halved slope and HR 0.57 for kidney failure (Perkovic 2025, PMID 39453772) (Barratt 2026, PMID 41910396) — but not in FSGS (Rheault 2023, PMID 37921461)? Surrogate validity appears to be disease- and mechanism-specific rather than a property of the marker.

  • Does terminal C5 inhibition deliver the kidney-function benefit that factor B inhibition does? Both reduce proteinuria by ~30–40%, but only iptacopan has been tested to a kidney-failure endpoint (Lafayette 2025, PMID 39455063).

  • With multiple mechanistically distinct agents now showing proteinuria benefit in IgA nephropathy, in what order should they be used, and does any combination improve clinical outcomes? A short crossover trial compared ambrisentan, henagliflozin and their combination on proteinuria (Chen 2026, PMID 41949916), but no phase 3 comparative outcome trial answers the sequencing question.

  • Why is belimumab's kidney benefit confined to proliferative lupus nephritis with baseline uPCR below 3 g/g, with no effect in sub-epithelial deposits or heavier proteinuria (Rovin 2022, PMID 34560137)? Phenotype-located effects of this kind are rarely sought in other glomerular diseases.

  • How should a therapy whose main value is steroid sparing and relapse prevention rather than superior remission induction be evaluated (Geetha 2025, PMID 40814647)?
  • Does the strict AURORA 1 composite — proteinuria target plus function stability plus steroid withdrawal — set a standard that older lupus nephritis trials cannot be compared against (Rovin 2021, PMID 33971155)?

References

  1. Torres et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407-2418. PMID 23121377
  2. Torres et al. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2017;377(20):1930-1942. PMID 29105594
  3. Lafayette et al. Targeted-release budesonide in primary IgA nephropathy: NefIgArd 2-year results. Lancet. 2023;402(10405):859-870. PMID 37591292
  4. Rovin et al. Sparsentan versus irbesartan in IgA nephropathy: PROTECT 2-year results. Lancet. 2023;402(10417):2077-2090. PMID 37931634
  5. Rheault et al. Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis. N Engl J Med. 2023;389(26):2436-2445. PMID 37921461
  6. Benson et al. Diagnostic utility of genetic testing in patients undergoing renal biopsy. Cold Spring Harb Mol Case Stud. 2020;6(5). PMID 32723786
  7. Granhoj et al. Family History is Important to Identify Patients with Monogenic Causes of Adult-Onset CKD. Nephron. 2022;146(1):49-57. PMID 34515170
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  9. 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
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  11. Cirillo et al. A population-based approach for the definition of chronic kidney disease: CKD Prognosis Consortium. J Nephrol. 2012;25(1):7-12. PMID 22038337
  12. Matsushita et al. Cohort profile: the chronic kidney disease prognosis consortium. Int J Epidemiol. 2013;42(6):1660-1668. PMID 23243116
  13. CKD Prognosis Consortium et al. Estimated GFR, Albuminuria, and Adverse Outcomes: individual-participant data meta-analysis. JAMA. 2023;330(13):1266-1277. PMID 37787795
  14. Inker et al. Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities. Am J Kidney Dis. 2019;73(2):206-217. PMID 30348535
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