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)

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

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

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

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.    

Kidney International 2015 88, 146-151DOI: (10.1038/ki.2015.71) Copyright © 2015 International Society of Nephrology Terms and Conditions

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

Polycystic Kidney Disease

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

N Engl J Med Volume 371(24):2255-2266

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.

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

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

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

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.

N Engl J Med Volume 363(9):820-829

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.

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

©2016 by American Society of Nephrology

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

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

©2016 by American Society of Nephrology

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

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

Original Article Tolvaptan in Patients with Autosomal Dominant

Polycystic Kidney Disease

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

N Engl J Med Volume 367(25):2407-2418

December 20, 2012

Patient Enrollment and Outcomes.

Torres VE et al. N Engl J Med 2012;367:2407-2418

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

Torres VE et al. N Engl J Med 2012;367:2407-2418

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

Torres VE et al. N Engl J Med 2012;367:2407-2418

Most Common Adverse Events and Serious Adverse Events.

Torres VE et al. N Engl J Med 2012;367:2407-2418

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.

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.

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’.

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.

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.