 Introduction

 Experimental studies
 Human studies
 Introduction
 Experimental studies
 Human studies
 ADPKD
 ARPKD
 Cystic renal dysplasia
 Medulary cystic disease
 Dialysis Cystic disease
 Simple cyst
Epidemiology
 12.5 million people worldwide
 Population-based epidemiologic studies with

ascertainment of autopsies have estimated

that ADPKD affects 1 in 400 to 1000 live
births
 Other studies based on clinical registry data

suggest lower prevalence rates, ranging from

1 in 543 to 1 in 4000. 
Major milestones in ADPKD
Major milestones in ADPKD
ADPKD Pathophysiology
 Mutation PKD1, PKD2

Loss of ciliary function of PC1, PC2

Reduced Calcium signaling

Increase adenilat cyclase activity+decrease fosfodiesterase activity

Increased cellular AMP

Promote PKA activity

Proliferation and fluid secretion

Increased cell proliferation and fluid secretion
ADPKD Pathophysiology

Am J Kidney Dis. 2016 May; 67(5): 792–810.

Cyst growth mechanism
1. ULTRASONOGRAFIE:
Original Ravine's PKD1 diagnostic criteria
-15–29 ≥2 cysts, unilateral or bilateral
-30–39 ≥2 cysts in each kidney
-40–59 ≥2 cysts in each kidney
-≥60 ≥4 cysts in each kidney
Revised unified diagnostic criteria
-15–29 ≥3 cysts, unilateral or bilateral
-30–39 ≥3 cysts, unilateral or bilateral
-40–59 ≥2 cysts in each kidney
-≥60 ≥4 cysts in each kidney
Revised criteria for exclusion of diagnosis
-15–29 ≥1 cyst
-30–39 ≥1 cyst
-40–59 ≥2 cysts
-≥60 ≥4 cysts in each kidney
2. DIAGNOSTIC GENETIC- identificarea genelor

+ ISTORIC FAMILIAL POZITIV

Disease progression in ADPKD
 Figure 1
ADPKD progression factors

The Lancet 2015 385, 1993-2002DOI: (10.1016/S0140-6736(15)60907-2)

Copyright © 2015 Elsevier Ltd Terms and Conditions
Progression score calculation
 Classification by HtTKV0 and age at HtTKV0 predicts the change in eGFR over time in class 1
patients.
66.9%

47.1

37.8

11%

2.4%

María V. Irazabal et al. JASN 2015;26:160-172

©2015 by American Society of Nephrology

 Classification by HtTKV0 and age at HtTKV0 predicts renal survival in class 1 patients.

María V. Irazabal et al. JASN 2015;26:160-172

©2015 by American Society of Nephrology

ADPKD treatment strategies
Current Human Clinical Trials for
Assessing Efficacy for ADPKD
Comparison of potential treatments in PKD
 Introduction
 Experimental studies
 Human studies
RAS System and ADPKD
Antisense-mediated angiotensinogen inhibition slows polycystic kidney disease in
mice with a targeted mutation in Pkd2

Am J Physiol Renal Physiol. 2015 Feb 15; 308(4): F349–F357.

mTor inhibition- cystic disease
regression in PKD1 KO mice
 Introduction
 Experimental studies
 Human studies
Effects of RAAS blockade and statin on the cumulative incidence of CVA
in patients with ADPKD.

Oncotarget. 2017 Jun 27;8(37):61570-61582

Effect of therapeutic interventions
Figure 3 on cyst progression

The Lancet 2015 385, 1993-2002DOI: (10.1016/S0140-6736(15)60907-2)

Copyright © 2015 Elsevier Ltd Terms and Conditions
BMC Nephrol. 2017; 18: 268.
 The Phase III, multicenter, international,
randomized-withdrawal, placebo-controlled,
double-blind trial compared the efficacy and
safety of tolvaptan (45 to 120mg/day) to
placebo. 
 A total of 1,370 patients were randomized to

either tolvaptan or placebo and were treated

for a period of 12 months.
Effect of tolvaptan on kidney function by CKD stage. 

Clin J Am Soc Nephrol. 2016 May 6; 11(5): 803–811.

Effect of tolvaptan on total kidney volume by CKD stage. 

Clin J Am Soc Nephrol. 2016 May 6; 11(5): 803–811.

From: Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly
progressive patients? Application of the PROPKD score in the TEMPO trial
Nephrol Dial Transplant. Published online July 19, 2017. doi:10.1093/ndt/gfx188
Nephrol Dial Transplant | © The Author 2017. Published byOxford University Press on behalf of ERA-EDTA.This is anOpen
Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial reuse, distribution, and reproduction in
Somatostatin analogs in ADPKD

Am J Kidney Dis. 2016 May; 67(5): 792–810.

 455 Patients were enrolled at four University Medical
Centers in the Netherlands between June 2012 and March
2015.
 Patients were randomly assigned in a 1:1 ratio to receive
standard care (control group) or subcutaneous lanreotide
injections (120 mg,), every 28 days for 120 weeks,
 Several cases of hepatic cyst infection developed only in
ADPKD patients in the lanreotide group
 A literature review also suggested an increased risk for
hepatic cyst infection during the use of somatostatin
analogs
 Final result …

Drug Saf. 2017; 40(2): 153–167.

-rezultatele studiului CRISP: rata de crestere a rinichilor este exponentiala
si un bun predictor al declinului functiei renale (IRM)
-concluzia: utilizarea volumului renal ca marker de progresie a bolii in
trialurile clinice pentru ADPKD.
 În 1729, astronomul francez
Jean Jacques d'Ortous de
Mairan a plasat o plantă
mimosa pe întuneric și a
observat că frunzele încă se
deschid și se închid ritmic la
ora corespunzătoare a zilei,
sugerând o origine endogenă a
ritmului zilnic.
 În anii 1970, Seymour Benzer și studentul său, Ronald Konopka, au
demonstrat că mutațiile dintr-o genă necunoscută au întrerupt
ceasul circadian al muștelor de fructe.
 Au numit această genă period.

 În 1984, Jeffrey Hall și Michael Rosbash și Michael Young au reușit să

izoleze gena period.
 Jeffrey Hall și Michael Rosbash au descoperit
că PER, proteina codificată de gena period, se
acumulează în timpul nopții si este degradată
în timpul zilei. 

 Astfel, nivelurile de proteine ​PER oscilează pe

un ciclu de 24 de ore, în sincronizare cu
ritmul circadian.
 Printr-o buclă
inhibitorie de
feedback, proteina PER
ar putea să prevină
sinteza proprie și
astfel să își regleze
propriul nivel într-un
ritm continuu, ciclic.
 Prin descoperirile celor trei laureați, cu
elucidarea unui mecanism fiziologic
fundamental, biologia circadiană s-a
dezvoltat într-un câmp vast și foarte dinamic
de cercetare, cu implicații asupra terapiei
genice.