- Autosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple bilateral renal cysts that lead to kidney enlargement and failure. It has a prevalence of 1 in 400 to 1000 live births. - The disease is caused by mutations in the PKD1 and PKD2 genes which code for polycystin proteins 1 and 2. These proteins are involved in cellular signaling pathways regulating cell proliferation and adhesion. Loss of function of these proteins results in focal cyst formation in the kidneys. - Current treatments aim to slow cyst growth and decline in kidney function. Vasopressin receptor antagonists like tolvaptan have shown some efficacy in reducing total kidney volume increase in

1. Molecular targets of therapy in
Rupin Kumar
Medical Student, 5thYear
Rabindra NathTagore Government Medical College,Udaipur
India

2.  ADPKD is a multisystem disorder
characterized by multiple, bilateral renal
cysts associated with cysts in other organs,
such as liver, pancreas, and arachnoid
membranes.
 Incidence: 1 in every 400 to 1000 live births.
 Typically leads to renal failure mainly due to
continued enlargement of cysts.

3. A Gross Comparison!
Markedly
enlarged
polycystic kidneys
in comparison to a
normal kidney in
the middle.

4. Renal
manifestation
s
Decline in
urine
concentratin
g ability
manifesting
clinically as
polyuria,
polydipsia,
nocturia
(60%)
Hematuria
(50%)
Hypertension
(60-100%)
Nephrolithi
asis, mainly
uric acid
(25%)
Proteinuria
(>300mg/da
y, 48%)
Flank and
abdominal
pain

5. PKD1
 Located on Chromosome
16
 Codes for Polycystin 1
protein (PC1)
 Associated with more
severe phenotype
 Incidence: 85%
PKD2
 Located on Chromosome 4
 Codes for Polycystin 2
protein (PC2)
 Less severe phenotype
 Incidence: 15%
*PKD1 mutation maybe
associated with deletion of TSC2
gene in 2/3rd, CONTIGUOUS
GENE SYNDROME

6. Wilson, P. D. N Engl J Med 2004;350:151-164
Age(inyears)

7. N-terminal
GPCR,
proteolytic site
C-terminal,
binds to β-
catenin
Locations:
PC1: Cilia,
Basolateral
membranes, inter-
membrane junctions.
Helps in cell-cell
adhesions.
PC2: non-selective
cation channel,
permeable to
Calcium.
Located mainly in
SER.
Siteofinteraction

8.  Genetic defects + in all cells; cysts only in
<10% tubules Focal Cystic Dilation.
 The concept of loss of heterozygosity:
Timing of
inactivation
of PKD1
Second Hit
Mutations
Loss of
Heterozygosity

9. Gallagher et al, Adv Chronic Kidney Disease 2010 March; 17(2): 118-130

10. Gallagher et al, Adv Chronic Kidney Disease 2010 March; 17(2): 118-130
A, Kidneys of
Pkd1cond/cond;tamoxifen-Cre+ mice
with inactivation of Pkd1 induced at
postnatal day 12 (P12) became cystic
within 3 weeks (left panel), whereas if
Pkd1 inactivation
occurs at P14, they remained normal
3 months later (right panel)
B,C, Pkd1
inactivation in adult kidneys results in
late-onset renal cystic disease.
Kidneys from
Pkd1cond/cond;tamoxifen-Cre+ mice
harvested 3 months (B) or 6 months
(C) after Pkd1
inactivation was induced at 6 weeks
of age

11.  Translocation of Na-KATPase pumps
 Role of cAMP and intracellular calcium
 Mammalian target of rapamycin (mTOR)
 Role of cilia
 Tubular hyperplasia
 Cell planarity changes

12.  Apical-lateral distribution of Na-KATPase is a
normal transient feature of early collecting
tubule development.
 But, apical membrane distribution PERSISTS
in cystic kidneys.
 Maybe due to cellular dedifferentiation or
cellular immaturity.
 Trans-tubular import of fluid into cysts.

13. Expression of Na+/K+-ATPase
subunits during control and cystic
CPK renal tubular development.
[Immunoperoxidase stain
(brown), counterstained with
hematoxylin. A and C, x 165; B
and D, x 130.] (A) Control day 3
proximal tubules demonstrate
basal-lateral
expression of Na+/K+-ATPase al
subunit. (31 subunit expression
was identical. (B) CPK day 3
cystic proximal tubules, as well as
unaffected
proximal tubules in the field,
demonstrate basal-lateral
Na+/K+-ATPase al subunit
expression. (31 subunit
expression was identical. (C)
Control
day 8 outer cortical collecting
tubule demonstrates apical, as
well as lateral, (31 subunit
expression. Note the purely
basal-lateral staining of
other collecting tubules in the
field. al subunit expression was
identical. (D) CPK day 8 cystic
outer cortical collecting tubule
demonstrates
apical, as well as lateral, (81
subunit expression. Note the
purely basal-lateral staining of no
cystic tubules in the field. al
subunit expression
was identical.

14. PC2
overexpression
aided by PC1
Increases
intracellular
calcium
Reduced intracellular calcium
Inhibits calcium
dependent
phosphodiesterases
Stimulates
Adenyl Cyclase
Increased cAMP
Increased
cAMP
CFTR dependent
fluid and chloride
secretion
Increases
aquaporin
expression (?)
Cell proliferation
through activation
of MAP-kinases
Calcimimetics,
increased CaSR
activation
IncreasingGsPCR antagonist,
e.g.Vasopressin or GiPCR
agonist, eg. Octreotide
Activated by 2-
acylamino-3-
thiophenecarboxylase
Cystic Fibrosis

15. Growth Factors
PI3K
AKT
Phosphorylates
TSC1/TSC2
GTPase action of
Rheb
+mTOR Complex
Cell Proliferation
and angiogenesis
mTOR
inhibitors

16. •Located on renal tubular epithelial cells.
•Senses fluid flow-mediated deflection of
ciliary axoneme by increased influx of
calcium.
•But PC1 inactivation causes defective
sensory perception of flow.
•Reduced intracellular calcium, increased
cAMP!

19. Vasopressin Receptor Antagonists:
OPC 31260,Tolvaptan
 Multicenter, placebo-controlled, double-blinded trial (TEMPO 3:4)
 Inclusion: 18 to 50 years, GFR >60ml/min,TKV >750ml.
 Dose: 60 to 120mg daily, 2:1 Drug: Placebo
 Results after 3 years:
Tovalptan Placebo
Increase inTKV 2.8% 5.5%
Decline in kidney function -2.61 mg/ml -3.81mg/ml
Adverse effects noted withTolvaptan:
1. Increased liver enzymes (4.9%)
2. Chest pain (0.8%)
3. Headache (0.5%)
TorresVE, Chapman AB, Devuyst O et al.Tolvaptan in patients with autosomal dominant polycystic kidney disease. NEJM 2012; 367:407

20. Increased fluid intake:
Suppresses vasopressin levels.
 Pilot study to compare acute and chronic (atleast 3L/day) water loading
on urine osmolality and cAMP concentrations in 13 subjects with ADPKD,
10 healthy controls.
 Excluded: Antidiuretic use, GFR <60.
Results:
 Chronic water load increased urine volume to mean of 3.1L/day and
decreased osmolality to 270 mosm/day inADPKD subjects.
 Acute water load reduced 24-hr cAMP excretion.
 Less practical feasibility, monitor Na levels.
Barash I et al,A pilot study to evaluate changes in the urine osmolality and urine cAMP in response to acute and chronic water
loading in ADPKD.Clin J Am Nephrol 2010; 5:563.

21. Somatostatin:
 RCT on 34 patients with ADPKD with Somatostatin or placebo.
 Large multicentric trials required.
 Results after one year:
Somatostatin Placebo
Mean kidney
volume
Stable, 0.25%
increase
8.60% increase
GFR Reduced to same
degree
Reduced to same
degree
Hogan et al. Randomized ClinicalTrial of long-acting Somatostatin for ADPKD and liver disese. J Am Soc Nephro 2010; 21: 1052

22. mTOR inhibitors:
 *Double blind, two year. 431 patients with PKD (mean GFR 55 ml/min/1.73m2)
with placebo or everolimus.
 Increase in protein: creatinine in Everolimus group.
 S/e: Leukopenia, thrombocytopenia, hyperlipidemia.
**Trial 2:
 Open-label RCT, 18 months. 100 patients with PKD (mean GFR 70 ml/min) with placebo or
sirolimus.
 NO CHANGE INTKV OR GFR after 18 months.
 Albumin: creatinine 38% increased in Sirolimus group.
***Novel strategy:
Kidney-targeted folate-conjugated form of rapamycin inhibited mTOR activity in the kidney but
not in other organs in a mouse model.
Everolimus Placebo
Increase inTKV 230ml 310ml
Decrease in GFR 8.9ml/min 7.7 ml/min

23.  PPAR agonists
 MAP kinase inhibitors
 EDGF inhibitors
 Lovastatin
 Methylprednisolone
 Amiloride and caffeine restriction

24. Thank you
for giving me
this
opportunity!