sociedad)norte)de)nefrología bilbao)25926)de)noviembre)2016) · 2016. 11. 29. · conclusions •...

Poliquistosis renal

Sociedad Norte de Nefrología Bilbao 25-‐26 de Noviembre 2016

60 años. RemiBdo desde otro Hospital con el diagnósBco de ESRD por ADPKD Crs 4 mg/dl

Riñones con múlBples quistes, de 10 cm de eje longitudinal Microhematuria y proteinuria no nefróBca persistente. Varios miembros de la familia con microhematuria, uno de ellos diagnosBcado mediante Biopsia de Enfermedad de la membrana basal delgada

Table 1 Characteristics of the ciliopathies

Kurschat, C. E. et al. (2014) An approach to cystic kidney diseases: the clinician’s view Nat. Rev. Nephrol. doi:10.1038/nrneph.2014.173

Figure 4 Relationship between age and total kidney volume (TKV) in patients with autosomal dominant polycystic kidney disease

Grantham, J. J. & Torres, V. E. (2016) The importance of total kidney volume in evaluating progression of polycystic kidney disease Nat. Rev. Nephrol. doi:10.1038/nrneph.2016.135

Part a reproduced with permission from Massachusetts Medical Society © Jared J. Grantham et al. Volume progression in polycystic kidney disease. N. Engl. J. Med.

354, 2122–2130 (2006). Part b reproduced with permission from PLOS © Dongping Chen. et al. PLoS ONE 9, e92232 (2014), which is licensed under a Creative Commons Attribution 4.0

International Licence. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

Figure 5 Hypothetical inverse relationship between total kidney volume (TKV) and glomerular filtration rate (GFR) in patients with autosomal dominant polycystic kidney disease (ADPKD)


Figure 6 Hypothetical effect of starting therapy for autosomal dominant polycystic kidney disease (ADPKD) at 18 years or 35 years of age


Diagram depicting the spectrum of predictors for rapid renal disease progression in ADPKD. Shaded ovals represent the most established predictors.

Robert W. Schrier et al. JASN 2014;25:2399-2418

©2014 by American Society of Nephrology

§  PROBLEMAS: Dificulta para acceder a ESTUDIO GENÉTICO y alto coste.

Pathogenetic role of RAAS in ADPKD.

Robert W. Schrier JASN 2009;20:1888-1893

1985-1992 a 1992-2001: 〉10 años para desarrollar ERCT.

Original Research |15 November

1991

Reversible Renal Failure Associated with Angiotensin-

Converting Enzyme Inhibitors in Polycystic Kidney Disease

Original Article Angiotensin Blockade in Late Autosomal Dominant

Polycystic Kidney Disease

Vicente E. Torres, M.D., Ph.D., Kaleab Z. Abebe, Ph.D., Arlene B. Chapman, M.D., Robert W. Schrier, M.D., William E. Braun, M.D., Theodore I. Steinman, M.D., Franz T. Winklhofer, M.D., Godela Brosnahan, M.D., Peter G. Czarnecki, M.D., Marie C. Hogan, M.D., Ph.D., Dana C. Miskulin, M.D.,

Frederic F. Rahbari-Oskoui, M.D., Jared J. Grantham, M.D., Peter C. Harris, Ph.D., Michael F. Flessner, M.D., Ph.D., Charity G. Moore, Ph.D., M.S.P.H., Ronald D. Perrone, M.D., for the HALT-PKD Trial Investigators

N Engl J Med Volume 371(24):2267-2276

December 11, 2014

Study Overview

•  This trial tested single versus dual inhibition of the renin–angiotensin–aldosterone system in ADPKD.

•  ACE-inhibitor monotherapy controlled blood pressure in most patients. •  Adding an angiotensin II–receptor blocker did not alter the decline in

estimated GFR.

Effect of Lisinopril–Telmisartan, as Compared with Lisinopril–Placebo, on the Time to Primary-Outcome Events and on the Estimated Glomerular Filtration Rate (eGFR).

Torres VE et al. N Engl J Med 2014;371:2267-2276

Original Article Blood Pressure in Early Autosomal Dominant


Robert W. Schrier, M.D., Kaleab Z. Abebe, Ph.D., Ronald D. Perrone, M.D., Vicente E. Torres, M.D., Ph.D., William E. Braun, M.D., Theodore I.

Steinman, M.D., Franz T. Winklhofer, M.D., Godela Brosnahan, M.D., Peter G. Czarnecki, M.D., Marie C. Hogan, M.D., Ph.D., Dana C. Miskulin, M.D.,

Frederic F. Rahbari-Oskoui, M.D., Jared J. Grantham, M.D., Peter C. Harris, Ph.D., Michael F. Flessner, M.D., Ph.D., Kyongtae T. Bae, M.D.,

Charity G. Moore, Ph.D., M.S.P.H., Arlene B. Chapman, M.D., for the HALT-PKD Trial Investigators


December 11, 2014

Enrollment, Randomization, and Follow-up of the Study Participants.

Schrier RW et al. N Engl J Med 2014;371:2255-2266

Changes in Total Kidney Volume and Estimated Glomerular Filtration Rate (eGFR) during Follow-up and Subgroup Analyses, According to Blood-Pressure Group.


Changes in Total Kidney Volume and eGFR during Follow-up, and Subgroup Analyses, According to Treatment Group.


Conclusions

•  In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume.

•  As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion.

N Engl J Med 2010; 363: 830-‐841

N= 399

§  FG: 30-‐89 ml/min y >90. Vol> 1000 ml.

§  Volumen 2 años: 230 ml vs 310; p 0.06.

§  FG: -‐ 8.9 ml/min/y vs -‐7.7 p< 0.15.

§  Más efectos 2ª en grupo io.

Original Article Sirolimus and Kidney Growth in Autosomal

Dominant Polycystic Kidney Disease

Andreas L. Serra, M.D., Diane Poster, M.D., Andreas D. Kistler, M.D., Fabienne Krauer, B.S., Shagun Raina, M.S., James Young, Ph.D., Katharina M. Rentsch, Ph.D., Katharina S. Spanaus, M.D., Oliver Senn, M.D., M.P.H., Paulus Kristanto, Ph.D., Hans

Scheffel, M.D., Dominik Weishaupt, M.D., and Rudolf P. Wüthrich, M.D.


August 26, 2010

Total Kidney Volume

Serra AL et al. N Engl J Med 2010;363:820-829

Study flow diagram.

Piero Ruggenenti et al. CJASN 2016;11:785-794

GFR changes during the study according to treatment groups.



Individual patient total kidney values at baseline and 12 months of follow-up according to treatment groups.



Changes in twenty-four–hour albuminuria and proteinuria during the study according to treatment groups.


Original Article Tolvaptan in Patients with Autosomal Dominant


Vicente E. Torres, M.D., Ph.D., Arlene B. Chapman, M.D., Olivier Devuyst, M.D., Ph.D., Ron T. Gansevoort, M.D., Ph.D., Jared J. Grantham, M.D., Eiji Higashihara, M.D., Ph.D., Ronald D. Perrone, M.D., Holly B. Krasa, M.S., John Ouyang, Ph.D., Frank S. Czerwiec, M.D., Ph.D., for the TEMPO 3:4

Trial Investigators


December 20, 2012

Patient Enrollment and Outcomes.


Effect of Tolvaptan on the Annual Slopes of Total Kidney Volume and Kidney Function.


Effect of Tolvaptan on the Time to Multiple Events Associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD).


Most Common Adverse Events and Serious Adverse Events.


Conclusions

•  Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events.

§  Estudio randomizado doble-‐ciego. PravastaBna 20-‐40 mg frente a placebo.

§  Mecanismo fisiopatológico desconocido.

§  8-‐22 años. 3 años de seguimiento.

73 ENSAYOS EN MARCHA EN ADPKD

Markers used to assess prognosis in ADPKD. Shaded rectangles represent the best-validated markers (adapted from ref. [24]).

Ron T. Gansevoort et al. Nephrol. Dial. Transplant. 2016;31:337-348

© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

The Mayo classification for prediction of disease progression in ADPKD by htTKV and age.



Algorithm to assess indications for initiation of treatment in ADPKD. The EMA label for tolvaptan states that this drug is indicated for ‘ADPKD patients with CKD stages 1–3 and

evidence of rapid disease progression at initiation of treatment’.



CÓMO INICIAR, TITULAR Y MANTENER EL TRATAMIENTO CON TOLVAPTÁN?

§  El inicio de Tolvaptán se suele acompañar de una “caída” del eGFR (tras 3 semanas con 120 mg: -‐0.7-‐7.8 ml/min ≈ al observado con IECA/ARA II). §  No hay marcadores a corto plazo que hablen de la eficacia del tratamiento. §  Ensayar como en los estudios (30/15; 45/15; 60/30; 90/30 mg). §  TEMPO 3:4: 55%-‐120 mg; 21%-‐90 mg; 24%-‐60 mg-‐-‐ ✗: 95 mg. §  23% abandonaron el estudio por efectos 2º (7.4% por efectos diueréBcos-‐1º tres meses).

Irazabal MV, Kidney Int 2011;80: 295-‐301

Rapid decrease in cys9c fluid secre9on 3 SEMANAS DE TRATAMIENTO

-‐ 49% -‐26%

“A phase 3b, mul?-‐center, randomized-‐withdrawal, placebo-‐controlled, double-‐blind, parallel-‐group trial to compare the efficacy and safety of Tolvaptan (45-‐120 mgday, split dose) in subjects with chronic kidney disease between late Stage 2 to

early Stage 4 due to Autosomal Dominant Polycys?c Kidney Disease”

CRITERIOS DE INCLUSIÓN: §  Hombres o mujeres entre 18-‐55 años con eGFR: 25-‐65 ml/min ó

§  Hombres o mujeres entre 56-‐65 años con eGFR: 25-‐44 ml/min.

§  No toma previa de Tolvaptán.

§  DiagnósBco de ADPKD por los criterios modificados de Pei-‐Ravine.

CRITERIOS DE EXCLUSIÓN: §  Mujeres embarazadas o que no quieran adoptar medidas anBconcepBvas. §  Necesidad de uso crónico de diuréBcos. §  Enfermedad hepáBca o alteración del perfil hepáBco. §  Pacientes con DM avanzada (proteinuria significaBva, reBnopava, nefropava) con HbA1c> 7.5%.

“A phase 3b, mul?-‐center, randomized-‐withdrawal, placebo-‐controlled, double-‐blind, parallel-‐group trial to compare the efficacy and safety of Tolvaptan (45-‐120 mgday, split dose) in subjects with chronic kidney disease between late Stage 2 to

early Stage 4 due to Autosomal Dominant Polycys?c Kidney Disease”

²  1.300 pacientes en 220 centros.

²  Duración: 12 meses, 6 semanas de Btulación de dosis (30/15; 45/15; 60/30; 90/30 mg). Duración total de 15-‐17 meses.

²  Primary Efficacy Endpoint: Cambios en eGFR pre y post-‐tratamiento.

²  Secondary Endpoints: Slope anual de eGFR.

²  Estudios de seguridad.

sociedad)norte)de)nefrología bilbao)25926)de)noviembre)2016) · 2016. 11. 29. · conclusions •...

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