P-Y Martin Jeudi 17 novembre 2017 Délémont

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1 P-Y Martin Jeudi 17 novembre 2017 Délémont
Le point sur le traitement de la Polykystose Rénale Autosomale Dominante en 2017 P-Y Martin Jeudi 17 novembre 2017 Délémont

2 Maladie polykystique autosomale dominante (ADPKD ou PKD)
Fréquente (1/400-1/1000) ubiquitaire, M=F Anomalies génétiques de protéines nommées polycystines (PKD1 85% /PKD2 15%) identifiées dans 90-95% des familles. 10-15% sans AF Kystes bilatéraux, issus de tous les tubules mais principalement tubes collecteurs. Symptomatique âge adulte 2 % symptomatique enfance ESRD âge median: 53.4 ans PKD1 ; 72.7 ans PKD2 Entre 45 et 70% des patients évoluent vers IRT avant 65 ans 10% des causes ESRD (4ème cause)

3 Diagnostic de PKD: US Si anamnèse familiale (AF)
Si AF, >40 et, <2 kystes, diagnostic exclu Si absence AF reins de grande taille, symétrique et kystes (>10 par rein), foie kystique Moins probable: Si absence AF, patient jeune (< 40 ans), reins non agrandis, peu de kystes, non symétrique, pas de kyste hépatique: Testing génétique à discuter dans ces situations (ou autre situation: donneur familial pour greffe) Ravine, JASN, 2009

4 Hypertension or urological complications before age 35 are predictors of ESRD
Treatment of Hypertension < age 35 First urological complication < age 35 Flank pains related to cysts, Cyst infection or Macroscopic Haematuria P<0.001 Yes No Median Age 54.1 yrs Median Age 67.9 yrs Cumulative Probability of Survival to ESRD Cornec-Le Gall_2015_J Am Soc Nephrol_The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease

5 Prise en charge ADPKD 2010 Traitement précoce HTA dont IEC
Prise en charge infections et lithiases TT ou chirurgie si douleurs Régime pauvre en sel, modéré en protéines et en caféine Apport liquidien > 2 L/j Suivi cardiovasculaire Détection et traitement complications extrarénales (anévrismes, diverticulites, prolapsus mitral, etc…)

6 Les différents progrès dans la prise en charge n’ont pas retardé l’IRT
Outcomes for ADPKD Patients Have Not Changed in Decades Les différents progrès dans la prise en charge n’ont pas retardé l’IRT 25 20 15 10 5 Mean age at start of RRT Incidence of RRT for ADPKD, per Million of Age-Related Population 1991−1995 1996−2000 2001−2005 2006−2010 56.6 57.4 58.3 58.1 0−4 5−9 10−14 15−19 20−24 25−29 30−34 35−39 40−44 45−49 50−54 55−59 60−64 65−69 70−74 75−79 80−84 ≥85 Presenter notes This study by Spithoven et al analysed changes in renal replacement therapy (RRT) incidence rates over time in patients with ADPKD Data was analysed from the European Renal Association-European Dialyses and Transplant Association Registry on 315,444 patients in 12 European countries between 1991 and 2010 Data are expressed per million of the age-related population Data was grouped into four 5-year periods; the different lines on the graph represent these different time periods No change over time was found in the incidence of RRT for ADPKD patients up to the age of 50; whereas the incidence of RRT in patients above the age of 70 years increased The authors concluded that the increased age at onset of RRT was most likely due to an increased access for elderly ADPKD patients or lower competing risk prior to the start of RRT rather than as a result of effective emerging treatments for ADPKD General notes Outcomes for ADPKD patients have not changed in decades, despite aggressive symptomatic treatment RRT, renal replacement therapy. ERA-EDTA Registry data: 12 countries with individual data, 206 million people Spithoven_2014_Kidney Int_Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease

7 Evolution naturelle de la PKD
PKD: changing the paradigm Evolution naturelle de la PKD Torres V. et al.

8 Classification of ADPKD according to imaging.
Imaging Classification of PKD patients using MR or CT images using ellipsoid equation Classification of ADPKD according to imaging. Irazabal_2014_J Am Soc Nephrol_Imaging Classification of Autosomal Dominant Polycystic Kidney Disease: A Simple Model for Selecting Patients for Clinical Trials

9 Suivi du volume rénal Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) 10 ans de suivis multicentriques radiologiques et cliniques Observations Les kystes sont déjà là dès l’enfance et leur croissance a lieu plus tard Plus de 90% patients montrent accroissement volume rénal de 4-5%/an alors que fonction rénale stable Volume rénal augmente proportionnellement aux volumes des kystes Volume rénal de base (1500ml) et taux élevé de croissance des kystes prédisent une progression défavorable Torres, CJASN, 2010 Grantham et al., NEJM, 2006

10 CRISP COHORT: relation volume/GFR
Grantham et al., NEJM, 2006 Grantham JJ et al Kidney Int 2008

11 The Mayo Clinic Classification http://www. mayo
Irazabal MV, et al. (2015) J Am Soc Nephrol. 26(1):

12 Mutations in PC1 or PC2 Lead to Cyst Formation (Cystogenesis)
Mutation of PC1 or PC2 genes Dysfunction PC1/PC2 causes: Increased cell proliferation Water movement into cysts Changes in cell shape from tubular to spherical Fluid-filled cysts form and, over time, a cyst-filled kidney develops with reduced functional activity Presenter notes This slide shows cyst formation in ADPKD at the level of the cell, nephron, and kidney Defects in the genes encoding PC1 or PC2 lead to aberrant gene transcription, cell proliferation, and chloride ion secretion, which in turn leads to the formation of fluid-filled cysts As cysts balloon out from individual nephrons, their collective effect leads to the displacement of renal tissue and the formation of a cyst-filled kidney with reduced functional activity General notes Mutated PC1 or PC2 results in abnormal ciliary function leading to disorientation of the mitotic spindle causing the cell to lose planar polarity Random cell division increases diameter rather than elongating the renal tubule Evolving cysts develop thickened tubule basement membranes and early fibrosis Collectively, cyst expansion leads to the displacement of normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity. Mutations in PC1 or PC2 lead to aberrant gene transcription, cell proliferation, and chloride (Cl-)-driven fluid accumulation1 Chapin_2010_J Cell Biol_The cell biology of polycystic kidney disease_Review

13 Le développement des kystes dépend de plusieurs voies cellulaires

14 There Are Three Main Mechanism-Based Strategies for the Treatment of ADPKD
Presenter notes Three main approaches are being investigated for the treatment of ADPKD: Inhibiting cell proliferation and therefore cyst growth Reducing cAMP levels, which plays a major role in the accumulation of cyst fluid and also cell proliferation Reducing fluid secretion, which is a major factor in cyst development General notes Inhibiting cell proliferation Reducing cAMP levels Reducing fluid secretion Adapted from: Chang_2012_Nephron Clin Pract_Mechanism-Based Therapeutics for Autosomal Dominant Polycystic Kidney Disease: Recent Progress and Future Prospects_Review Belibi_2010_Expert Opin Investig Drugs_Novel targets for the treatment of autosomal dominant polycystic kidney disease_Review

15 Effets de l’AVP sur la cellule tubulaire principale

16 Approches pour moduler réabsorption eau libre au niveau rénal

17 V2R antagonisms Pessi A JCEM 2013

18 V2R antagonism is effective to correct hyponatremia
Li B et al . Clin Drug Invest 2017

19 hyponatremia Hoorn EJ and Zietse R. JASN 2017

20 Basic Research in 1970’s Led to Development of Tolvaptan
2 1 1991/1992 2009 3,4 5 6 8 9 7 Presenter notes This slide provides a brief overview of the history of V2 receptor antagonists in ADPKD, from the perspectives of basic science of V1/V2 receptors, drug discovery of V1/V2 receptor anatagonists and the application of this knowledge to the development of V2 receptor antagonists for the management of ADPKD The top row shows the discovery of the V1/V2 vasopressin receptors in 1979, followed by the discovery of the pivotal role of cAMP in the development of murine PKD in 1997 The middle row shows the development of the first non-peptide V1 receptor antagonist in 1991, followed by the first V2 receptor antagonist in 1992 The bottom row shows how the discovery that V2 antagonists inhibit PKD in mice and rats provided the rationale for developing V1/V2 vasopressin receptor antagonists for the treatment of ADPKD Development of tolvaptan started in in 1999 when researchers tested tolvaptan in animal models of PKD, which led to the phase 3 TEMPO 3:4 study which completed in TEMPO 3:4 is an open-label tolvaptan-treatment extension of the TEMPO 3:4 trial Tolvaptan was approved in Japan in 2014 The Phase 3 REPRISE study and the Phase 3 Study 211 were both initiated in 2014 General notes Basic research from the late 1970’s provided the rationale for the development of V2 vasopressin receptor anatagonists and the development of tolvaptan Michell RH et al. (1979). Biochem Soc Trans. 7(5): Yamaguchi T et al. (1997). Am J Kidney Dis. 30(5): Yamamura Y et al. (1991). Science. 252(5005): Yamamura Y et al. (1992). Br J Pharmacol. 105(4): (Accessed 8 December 2014). Gattone VH, et al (1999) J Am Soc Nephrol. 24(3): Gattone VH, 2nd et al. (2003). Nat Med. 9(10): Torres VE et al (2012) NEJM 367(25): Torres VE., et al. (2014). J Am Soc Nephrol. 25: SA-OR038.

21 TEMPO 3:4: données de base
Age: ans eGFR: 82 ml/min/1.73 m2 dont 25% < 80 ml/min TKV: 1700 ml dont 20% < 1000ml 80% HTA Albuminurie dont 25% protéinurie 35% hématurie 50% douleurs rénales Torres V et al NEJM 2012.

22 Etude Tolvaptan Efficacy and safety in Management of ADPKD and its Outcome ( TEMPO)
Torres V et al NEJM 2012.

23 Effet du Tolvaptan sur le volume (A) et la fonction rénale (B) à 3 ans
Différence de perte: 1.2 ml/min/an Torres V et al NEJM 2012.

24 Effet sur la croissance des kystes et GFR selon stade IRC
Torres V et al CJASN 2016

25 Czerwiec FS, et al. (2013). J Am Soc Nephrol. 24. FROR103.
TEMPO 3:4: Tolvaptan Reduced Most Renal Complications (But Not Non-renal Complications) Presenter notes The percentage of patients reporting each of the 13 PKD-related complications are shown in this slide (in blue for tolvaptan-treated patients and in red if patients were assigned to placebo) Nine complications related to the kidney are grouped in the top of the figure, while those unrelated to the kidney are shown at the bottom The most frequently occurring complications were generally related to cystic kidney disease. For nearly all of these, the likelihood of having a complication was lower in the tolvaptan group. The only exceptions to this trend were hypertension, and those outcomes which were unrelated to the kidney cysts General notes Tolvaptan reduced most renal complications, but not non-renal complications in over the 3 years in TEMPO 3:4 *Significant Drop e.g., Dialysis, Transplant. Czerwiec FS, et al. (2013). J Am Soc Nephrol. 24. FROR103.

26 TEMPO 3:4: Aquaresis-related AEs Were More Common in Tolvaptan-treated Patients
While the incidence of aquaretic adverse events was higher in the tolvaptan group, the incidence of ADPKD-related adverse events was higher in the placebo group Adverse events occurring in >20% of patients are shown: Presenter notes Patients who received tolvaptan had a higher frequency of adverse events related to increased aquaresis (thirst, polyuria, nocturia, and polydipsia, as a result of the excretion of electrolyte-free water) In contrast, patients who received placebo had higher frequencies of adverse events related to ADPKD (kidney pain, hematuria, urinary tract infection, and back pain) 1. Torres VE et al. (2012). NEJM 367(25):

27 TEMPO 4:4 After 18 Months, No Difference in Liver Enzyme Elevations Between Treatment Groups
Risk of ALT elevation >3x ULN % of Subjects Presenter notes This slide shows the percentage of subjects with ALT elevations greater than 3 times the upper limit of normal After the first 18 months of treatment, the risk of liver enzyme elevations was not different from placebo and no irreversible hepatotoxicity was observed One subject met Hy's Law laboratory criteria) and 9 subjects (1.06%) experienced ALT/AST elevations >3 × ULN In all 3 Hy's Law cases, ALT and BT returned to normal with no chronic liver injury reported 1. Torres VE., et al. (2014). J Am Soc Nephrol. 25: SA-OR038.

28 TEMPO 3:4: Adherence in Tolvaptan-treated Patients
Adherence in patients treated with tolvaptan was good Patients, n (%) Tolvaptan (n = 961) Placebo (n = 484) Randomized 961 (100.0) 484 (100.0) Completed 36-mo visit on treatment 740 (77.0) 417 (86.2) Discontinued study treatment 221 (23.0) 67 (13.8) AE 148 (15.4) 24 (5.0) Patients withdrew consent 50 (5.2) 30 (6.2) Lost to follow-up 15 (1.6) 8 (1.7) Other 8 (0.8) 5 (1.0) Presenter note In TEMPO 3:4, 1,445 subjects were randomized, 961 to tolvaptan and 484 to placebo with over 77 % completing 3-years of tolvaptan treatment There was a 9% difference in discontinuation rates, 23% for tolvaptan and 14% for placebo. This difference is mostly due to aquaretic adverse events such as polyuria 1. Torres VE et al. (2012). NEJM 367(25):

29 Etude REPRISE Mai 2014-mars 2016
1370 patients PKD randomisé, double aveugle, placebo contrôlée. 18-55 ans avec eGFR ml/min/1.73m2 56-65 ans avec eGFR ml/min/1.73m2 Tolvaptan ou placebo 1:1 durant 1an. Visites mensuelles Torres VE et al N Engl J Med 2017 novembre 4

30 Etude REPRISE Torres VE et al N Engl J Med 2017 novembre 4

31 Perte de GFR moins importante dans le groupe Tolvaptan (1. 27 ml/min/1
Perte de GFR moins importante dans le groupe Tolvaptan (1.27 ml/min/1.73m2 par an) versus – 3.61 ml/min/1,73m2 Torres VE et al N Engl J Med 2017 novembre 4

32 Torres VE et al N Engl J Med 2017 novembre 4

33 Treatment benefit in an average TEMPO 3:4 patient
The JINARC clinical model estimates long term benefits across a variety of patients Otsuka has developed a model to predict the long term progression of ADPKD and potential benefit of tolvaptan treatment This model extrapolates the results seen in the TEMPO 3:4 study (31.6% annual reduction in decline of renal function) over a lifetime period to estimate the age at reaching ESRD with or without tolvaptan treatment In a patient cohort representing the average baseline characteristics from the TEMPO 3:4 study, the mean estimated delay to ESRD is 4.9 years (range: years#)* eGFR (mL/min/1.73m2) 90 Years from baseline 1 80 70 60 50 40 30 20 10 2 3 4 5 6 7 8 9 11 12 13 14 15 16 17 18 19 Control JINARC treatment ESRD Treatment benefit in an average TEMPO 3:4 patient JINARC No treatment Speaker notes: Using the ADPKD outcomes model, treatment with JINARC is predicted to have a positive clinical benefit in all patient types represented by the TEMPO 3:4 population ESRD is delayed by 4.9 years on average across the TEMPO population Across the range of patients modelled, preliminary estimates for outcomes, benefits and treatment durations vary based on age, renal enlargement and renal function at baseline #Range based on upper and lower 95% confidence bounds of the treatment effect (a mean constant relative annual reduction of 31.6%±7.8%); *without discontinuation from treatment 1. Robinson et al (2015) Poster presentation at ERA-EDTA, London

34 Gansevoort, R.T. et al. (2016). Nephrol. Dial. Transpl.

35 Traitement enregistré en Suisse depuis 2017

36 Limitations et Prix Critères idem à Recommendations européennes sauf âge.

37 Expérience genevoise 2017 Sélection sur dossiers des patients avec les critères Séance commune d’information aux patients avec présentation des données d’études. Contraintes du traitement Entretien individuelle avec néphrologue pour prise de décision Suivi mensuel si décision TT 6 patients sous TT depuis début 2017

38 Questions en suspens TT ralentit la survenue de l’IRT mais quel effet sur la morbidité et mortalité ? Coûts-bénéfices du traitement ?: pas de données: 24’000 CHF/an pour traitement à long-terme (10 ans -20 ans) Economicité d’un ralentissement de la progression de l’insuffisance rénale: pas de bons modèles si pas d’effets associés sur la mortalité ou morbidité. Comparaison avec coûts de la transplantation rénale Estimation canadienne > 100’000 $ per QALY

39 Evolution différente selon le poids de différents facteurs

40

41 Conclusions Le Tolvaptan est le premier traitement spécifique de la PKD. En moyenne, bien toléré en dépit des effets aquarétiques ( 23 % arrêt). Les effets sur la diurèse peuvent être incompatibles avec les conditions de vie du patient. Le suivi à long terme de la cohorte TEMPO 4:4 confirme l’effet persistant épargnant sur la perte de la fonction rénale. L’étude REPRISE montre une efficacité maintenue chez les GFR < 30 ml/min et chez les patients de plus de 50 ans. L’économie de fonction est substantielle (30%) mais reste insuffisant pour envisager chez la plupart des patients d’éviter l’IRT. L’effet sur les symptômes, notamment les douleurs, est un élément important. Il reste à démontrer l’effet de ce traitement sur la morbi-mortalité des patients. Le coût/bénéfice de ce traitement est questionnable et devra être rediscuté