Transcript Newer developments in PKD - A search for the gene is completed

Update on ADPKD and role of mTOR
inhibitors and other agents in its
management
ADPKD – Introduction
• Autosomal dominant polycystic kidney
disease (ADPKD) - one of the most
common inherited disorders in humans
• Most frequent genetic cause of renal
failure in adults
• Accounts for ~4% of end-stage renal
disease (ESRD).
Inheritance : Autosomal Dominant
Incidence 1 : 700 to 1 : 1000
In India : 10,00,000 cases
ADPKD - multisystemic and
progressive disorder
• Characterized by
formation and
enlargement of cysts in
the kidney and other
organs (eg, liver,
pancreas, spleen)
• Clinical features usually
begin in the third to fourth
decade of life, but cysts
may be detectable in
childhood and in-utero
Pathophysiology
• The main feature of ADPKD is bilateral
progressive cystic dilation of the renal
tubules, which may lead to end-stage
renal disease (ESRD)
• Hepatic cysts, cerebral aneurysms, and
cardiac valvular abnormalities also may
occur
PATHOGENESIS
• Modern ADPKD research started when
epithelial cell lining the cysts in kidneys of
ADPKD patients was successfully isolated
and maintained in “ex vivo” cultures.
• It is observed that cyst cells continue to
proliferate, secrete fluid and destroy the
surrounding normal tissue by expansion.
• Cyst fluid contains many hormonal
activities including ADH & EGF (Epidermal
Growth Factor)
The abnormality
• Approximately 85-90% of patients with
ADPKD have an abnormality on the short
arm of chromosome 16 (ie, ADPKD type 1
[ADPKD1])
• A second defect, termed ADPKD type 2
(ADPKD2), is responsible for 5-15% of
ADPKD cases and is found on the long
arm of chromosome 4
• A third genotype may exist, but no
genomic locus is assigned.
PKD1 and PKD2 expressed in
most organs and tissues
• Proteins encoded by PKD1 and PKD2 polycystin 1 and polycystin 2 - function together
to regulate the morphologic configuration of
epithelial cells
• The polycystins - expressed as early as the
blastocyst stage and expressed in a broad array
of terminally differentiated tissues
• The functions of the polycystins have been
scrutinized to the greatest extent in epithelial
tissues of the kidneys and liver and in vascular
smooth muscle.
Mortality/Morbidity
• The major cause of morbidity is progressive
renal dysfunctionIn - half of patients with ADPKD
undergo renal replacement therapy by age 60
years
• Cardiovascular pathology and infections account
for approximately 90% of deaths of those
patients treated by hemodialysis or peritoneal
dialysis and after renal transplantation
• Another cause of mortality is subarachnoidal
hemorrhage from intracranial aneurysms (ICAs).
This complication is rare and severe.
• Sex - ADPKD is slightly more severe in
males than in females, but it is not
statistically significant
• Age - Symptoms generally increase with
age. Children very rarely present with
renal failure from ADPKD
• The mean age of onset of ESRD in
patients with ADPKD1 is 53 years; in
patients with ADPKD2, it is 74 years.
Clinical manifestations
• Renal - A decrease in urine-concentrating
ability is an early manifestation of the
disease
• Microalbuminuria occurs in 35% of
patients with ADPKD
• Patients may develop renal failure, usually
in the fourth to sixth decade of life
Clinical manifestations – contd.
• Hypertension is one of the most common
early manifestations of ADPKD
• Pain - located in the abdomen, the flank,
or the back, is the most common initial
complaint
• Hematuria - frequently is the presenting
manifestation and usually is self-limited
• Stroke - aneurysm screening with
magnetic resonance angiography
Physical examination
• Palpable, bilateral flank masses occur in
patients with advanced ADPKD
• Nodular hepatomegaly occurs in those
with severe polycystic liver disease
• Symptoms related to renal failure (eg,
pallor, uremic fetor, dry skin, edema) are
rare upon presentation.
Diagnosis
• Renal USG - sensitivity 100% for subjects 30
years or older with a positive family history
• Diagnostic criteria - two or more cysts in one
kidney and at least one cyst in the contralateral
kidney in young subjects, but four or more in
subjects older than 60 years
• Most often, the diagnosis is made from a
positive family history and imaging studies
showing large kidneys with multiple bilateral
cysts and possibly liver cysts
Diagnosis contd.
• Before the age of 30 years - CT scan or
T2-weighted MRI is more sensitive for
detecting presymptomatic disease
because the sensitivity of ultrasound falls
to 95% for ADPKD type 1 and <70% for
ADPKD type 2
Treatment
• No specific medication is available for
ADPKD
• However, clinical trials with vasopressin 2
receptor antagonists (Tolvaptan),
somatostatin, rapamycin (sirolimus) and
some more agents are ongoing
• At present, treatment is largely supportive,
as there is no single therapy that has been
shown to prevent the decline in kidney
function.
Treatment
contd.
• Hypertension control - target blood pressure of
130/85 or less is recommended
• Lower levels reported to slow the rate of loss of
kidney function
• A multidrug approach that includes agents to
inhibit the renin-angiotensin system is frequently
required
• There is no compelling evidence to recommend
a low-protein diet, especially in patients with
advanced kidney dysfunction where optimizing
nutritional status is important
Treatment
contd.
• Lipid-soluble antimicrobials - trimethoprimsulphamethoxazole and quinolone antibiotics
that have good tissue permeation - preferred
therapy for infected kidney cysts
• Pain management - requires cyst drainage by
percutaneous aspiration, sclerotherapy with
alcohol, surgical drainage
• Patients with ADPKD appear to have a survival
advantage on either peritoneal or hemodialysis
compared to patients with other causes of ESRD
Treatment
contd.
• Those undergoing kidney transplantation
may require bilateral nephrectomy if the
kidneys are massively enlarged or have
been the site of infected cysts
• Posttransplantation survival rates are
similar to those of patients with other
causes of kidney failure, but patients
remain at risk for the extrarenal
complications of ADPKD.
Comparison of potential treatments for PKD
Compund
Mechanism
Molecular
target
PKD Models
Potential side Effect on
effects
liver cysts
Rapamycin
Antiproliferative mTOR
Han:SPRD
rat orpk mice
bpk mice
Human
Oral
mucositosis,
tremor,
hypertension
Vasopressin
V2R
antagonist
Inhibit fluid
secretion and
cAMP
cell proliferation
pcy mice PCK Hypernatremia,
No
rat Pkd2
thirst
Somatostatin
Inhibit fluid
secretion and
cAMP
cell proliferation
PCK rat
Human
Diarrhoea,
anorexia,
gallstones
Yes
Triptolide
Ca2+
signalling
Antiproliferative
(PC2dependent)
Pkd1 mice
(from E10.5)
Male infertility
Unknown
Roscovitine
Cyclincpk mice jck
Antiproliferative dependent
mice
kinases (Cdk)
Nausea,
transient
elevation of
creatinine,
hypokalemia
Unknown
Tyrosine
bpk mice
Diarrdoea,
Antiproliferative EGF receptor
kinase inhibitor
Han:SPRD rat rashes
Unknown
No
Batimastat
Inhibit matrix
degradation
Metalloprotein
Han:SPRD rat Arthralgia
ases
Unknown
Caspase
inhibitor
Antiaptosis
Caspases
Unknown
Pioglitazone
PeroxisomeproliferatorAntiproliferative activated
receptor(PPAR- )
Han:SPRD rat Diarrhoea
Pkd1 mice
(from E7.5)
Hypoglycemia,
weight gain,
Unknown
fluid retntion
TOLVAPTAN
• Otsuka Pharmaceutical (basic manufacturer of
Tolvaptan) is proceeding with multinational,
multicentre, phase III clinical trial to examine the
efficacy & safety of Tolvaptan in ADPKD
• Trials of tolvaptan in humans with ADPKD are
ongoing (Ref: Clin Ther. 2010 Jun;32(6):1015-32 )
• Approximately 1500 patients will be randomised
to either Tolvaptan or Placebo and will be
observed for the duration of 5 years
Mechanism of action (V2RA)
Tolvaptan has been shown to decrease cyst and kidney
volume.
• Shillingford also observed in a small group of
renal transplantation that size of cyst in native
ADPKD kidney significally reduced when treated
with sirolimus in comparison to CNI.
• Cincinnati Rapamycin Trial as well as ongoing
multicentre trial in UK & US has shown
favourable results in cysts of PKD in tuberous
sclerosis.
Sirolimus therapy in polycystic kidney
disease – A pilot study, Nov. 2009
Transplant proceedings A.R. Soliman, E.
Ismail, S. Zamil, Cairo university, Egypt.
Diagram : dysregulation & accumulation of mTOR in epithelial lining of cyst,
which may be final common pathway in cystogenesis.
Safety and tolerability of Sirolimus
treatment in patients with polycystic kidney
Andreas L. Serra, Andreas D. Kistler,
Daine Poster et al.
Nephrol Dia. Trans (2009) 3334-3342
Sirolimus reduces polycystic liver volume
in ADPKD patients
JASN 19, 631-638, 2008 Qian, Hui Du,
Bernal F. King et al.
SOMATOSTATIN
• Somatostatin has been shown to reduce
chloride and fluid secretion in cyst by inhibition
of adenylatecyclase & CAMP in epithelial cells of
cysts.
• Mario Negri Institute of Pharmacological
research in Italy will enroll 66 ADPKD patients to
test the efficacy of long acting somatostatin
octreotide LAR. This study will treat patients
with an estimated GFR > 40 ml/min./1.73 m2 and
follow the response of therapy by serial MRI
over 3 years.
Randomized clinical trial of long-acting
somatostatin for autosomal dominant
polycystic kidney and liver disease
• ADPKD(n-34) and ADPLD(n=8). Liver volume decreased
by 4.95%+/-6.77% in the octreotide group but remained
practically unchanged (+0.92%+/-8.33%) in the placebo
group (P=0.048).
• Among patients with ADPKD, total kidney volume
remained practically unchanged (+0.25%+/-7.53%) in the
octreotide group but increased by 8.61%+/-10.07% in
the placebo group (P=0.045). Changes in GFR were
similar in both groups.
• In summary, octreotide slowed the progressive increase
in liver volume and total kidney volume, improved health
perception among patients with PLD, and had an
acceptable side effect profile
• Ref: J Am Soc Nephrol. 2010 Jun;21(6):1052-61. Epub 2010 Apr 29
(R) - Roscovitine
• (R) – roscovitine is a (R) – sterioisomer of roscovitine.
-- Roscovitine is a low molecular weight
compound of 2, 6, 9 – tri-substituted
purine family.
-- 3 week course has long lasting
beneficial effect.
-- In clinical trials it is well tolerated.
• (R) – roscovitine is a protein kinase
inhibitor with preferenitial selectivity for
cyclin dependent kinase (CDKs)
Prevents phosphorylation of Rb (retinoblastoma) protein
Normalize the level of several cyclins
Prevent cell proliferation, transcription and  apoptosis
Prevents cyst progression.
Mechanism of action (Roscovitine)
Roscovitine on renal tubular epithelial cell
implications for autosomal dominant
polycystic kidney disease
• The cyclin kinase inhibitor roscovitine has shown
efficacy in treatment of murine PKD
• Renal tubular epithelial cells exposed to 'low'
concentrations of roscovitine showed minimal
apoptosis in association with markedly
increased levels of the antiapoptotic protein p21
• Data in this study provide a mechanistic
explanation of how roscovitine is effective in
PKD
• Ref: Am J Nephrol. 2009;29(6):509-15. Epub 2008 Dec 10
TRIPTOLIDE
• Natural Chinese herbal compound.
• Restores intracellular Ca2+ regulation in
cyst lining cells
• Thus inhibits c-AMP dependent cell
proliferation and water secretion.
Triptolide reduces cyst formation in a
neonatal to adult transition Pkd1 model
of ADPKD
• Daily injections with triptolide significantly
reduced the total number of cysts per kidney,
with a pronounced effect on the number of
microcysts and the overall cystic burden
• Additionally, renal function as assessed by blood
urea nitrogen levels was also improved in
triptolide-treated mice
• These results suggest that the model of ADPKD
is amenable to short-term kidney cyst formation
drug studies
• Ref: Nephrol Dial Transplant. 2010 Jul;25(7):2187-94.
Epub 2010 Feb 4
• How to monitor the therapeutic efficacy in
ADPKD.
- Very slowly progressive disease.
- Initially GFR remains stable.
- Once when Serum Creatinine exceeds
normal value GFR declines 5 ml/min/yr, leading
to ESRD within 10 years.
However individual variability is substantial.
• Consortium for Radiologic Imaging studies of PKD
(CRISP) followed 241 ADPKD patients by sequential
MRI measurement of cyst & renal volumes.
According to them, Volumetric kidney measurements by
MRI is the gold standard to determine disease
progression.
They also observed that Renal & cyst volumes
correlated inversely with GFR and directly to
hypertension and urinary albumin excretion.
Average annual increase in renal volume was 5.3%.
Cyst growth was more aggressive in young or who had
large renal volume at the time of diagnosis.
• Is it time to start clinical trials in ADPKD ?
Of course Yes..
ADPKD patients have waited enough &
suffered enough to find a cure of their
disease so any measure to halt the
progression of disease is highly warranted.
Phase I/II study is initiated by the cleveland
clinic which will enroll a total of 45 patients
and monitor the changes in iothalamate,
GFR and total kidney volume measured by
CT over the period of 12 months.
The patients will be divided into 3 groups.
Control (15), low dose of sirolimus (15)
(trough blood level 2-5 ng/ml) and high
dose of sirolimus (15) (trough blood level
5-8 ng/ml.).
• Other trial will treat 300 ADPKD patients with
everolimus. It has been started in Germany and
Austria and will follow ADPKD patients with
estimated GFR between 30 to 89 ml/min/1.73m2
(CKD stage II & III) for 2 years by repeated MRI.
Dose is the same as given in organ
transplantation.