Total Kidney Volume (TKV) in Autosomal Dominant Polycystic Kidney - - PowerPoint PPT Presentation

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Total Kidney Volume (TKV) in Autosomal Dominant Polycystic Kidney - - PowerPoint PPT Presentation

Dec 24, 2023 152 likes •299 views

Total Kidney Volume (TKV) in Autosomal Dominant Polycystic Kidney Disease as model for biomarker qualification Roslyn Simms NIHR Clinical Lecturer in Nephrology NIHR Clinical Trials Fellow Monday 23 rd April 2018 Background Total kidney

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Total Kidney Volume (TKV) in Autosomal Dominant Polycystic Kidney Disease as model for biomarker qualification

Roslyn Simms NIHR Clinical Lecturer in Nephrology NIHR Clinical Trials Fellow Monday 23rd April 2018

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  • Background
  • Total kidney volume (TKV) & Clinical relevance
  • CRISP studies
  • Timeline of Biomarker qualification
  • Summary
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80yr 68yr 56yr

ESRF

  • Commonest inherited kidney disease
  • 3rd commonest cause of renal failure (UK)
  • Disease progression is a patient priority
  • Monitoring progression currently – eGFR

late marker

  • Known genotype:

variability

Autosomal Dominant Polycys0c Kidney Disease (ADPKD)

Normal ADPKD

Cornec-Le Gall JASN 2013 Barua, JASN 2009

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Total kidney volume (TKV) in ADPKD

  • Gradual cyst development/years à ↑TKV
  • TKV clinically relevant, marker of progression:

1981: 1st measured (n43, CT) correlated 1/CrCl (Thomsen) 1992: 1st longitudinal (8yrs, n1, U/S) (Gabow) 2000: 1st prosp. (8yrs, n9, CT) rate ↑TKV 4%/yr (King)

  • Retrosp. (5yrs, n10, CT) faster ↑TKV α ↓GFR (Sise)
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Evidence of TKVs clinical relevance in ADPKD

  • TKV clinically relevant:

2001: Longit. (20yrs, n182, U/S): rate ↑TKV exponential and correlated hypertension (Fick-Brosnahan) 2002: 1st large longit. (7.8yrs, n229, U/S) rate ↑TKV 8.2%/yr, ↑TKV α ↓GFR (Fick-Brosnahan)

CRISP: Consortium for Radiologic Imaging Studies of PKD Aim - reliably & accurately measure TKV and TCV

  • detect change in TKV & TCV/short time frame
  • is TKV, TCV associated with ↓GFR

Annual MRI, 241 patients, 16-45yrs, eGFR>70ml/min

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Consortium for Radiologic Imaging Studies of PKD

CRISP1: 3yrs 4 centres (different vendors) recruiting (12/2000-10/2001) Standardisation protocol: Phantoms (known volume – gold std) 4 pts (travelling kidney, (TKV 540-2550ml) scanned each centre <1wk apart) Image transfer & analysis by analysts (2/phantoms, 3/pts) Gadolinium used

(Chapman 2003)

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CRISP outcomes & Key developments in Biomarker qualification

CRISP1(Chapman 2003): TKV measurement reliability 99.9% (phantoms) 0.998 (pts) TKV increased at 5.3%/year TKV greater with age, hypertension, urinary albumin exct. TKV inversely correlated with GFR (iothalamate) 2007: PKD Foundation & FDA: Acceptance of kidney growth as 1° outcome will encourage industry for PKD drug development 2009: Developed data standard to pool data & quantitative modelling methods (pharmacometrics, ADPKD specific)

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Timeline of progress of TKV becoming a prognostic biomarker in ADPKD

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2012: CRISP2 outcome evidence

CRISP2: n201, further 5yrs f/u, MRI every 2yrs, No Gad. Aim – does TKV predict ↓GFR?

Mean f/u 8yrs Baseline HtTKV>600ml/m predicts Stage 3CKD within 8yrs

1.0 0.5 0.0

  • 0.5
  • 1.0

1 2 3 4 6 8

GFR htTKV Follow up (yrs)

Change from baseline

Chapman 2012

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TKV as a prognostic biomarker in ADPKD

By 2012, evidence that TKV:

  • prognostic biomarker (CRISP studies)
  • useful all stages of drug dvp (1° endpoint TEMPO 3/4)

PKDOC (Polycystic Kidney Disease Outcomes Consortium) formally commenced Biomarker Qualification Used evidence (2355pts, collected over 40yrs): 2 longitudinal studies: CRISP1&2 3 US registries (Mayo, Universities Colorado & Emory)

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Timeline of Acceptance (FDA) of TKV as a prognostic biomarker in ADPKD

PKDOC à Biomarker Qualification Review Team (BQRT) 3/1/12: Letter of Intent (LOI) submitted to FDA COU: baseline TKV predicts pts at high risk of progression 6/3/12: LOI feedback (FDA) 24/9/12: Submit Qualification Plan (QP)/Briefing Document 11-12/12: Discussions/feedback 30/4/13: Revised QP submitted 28/6/13: PKDOC met BQRT. Further discuss (7-9/2013) 27/9/13: Final QP (+Qus to address) submitted to FDA 15/9/16: FDA approved TKV as prognostic biomarker Time frame (submissionàapproval): 56 months

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Timeline of Acceptance (EMA) of TKV as a prognostic biomarker in ADPKD

PKDOC à Biomarker Qualification Review Team (BQRT) 10/4/13: Letter of Intent (LOI) submitted to EMA COU: baseline TKV predicts pts at high risk of progression 30/4/13: Submit Qualification Plan (QP)/Briefing Document 13/6/13: Feedback & queries re QP 28/6/13: Written response to EMA queries 24/7/13: Submitted final QP 13/11/15: EMA approved TKV as prognostic biomarker Time frame (submissionàapproval): 31months

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Summary

  • Extensive evidence that the biomarker, TKV, is a clinically

relevant measure of disease progression in ADPKD

  • Combined with age & eGFR, TKV identifies patients early

who have a high risk of progressive decline. This facilitates clinical trial enrichment & drug development

  • The process of achieving regulatory approval of a

biomarker is time consuming

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Acknowledgements

Professor Albert Ong