Autosomal Dominant Polycystic Kidney Disease (ADPKD)
(Malattia policistica autosomica dominante o dell’adulto)
 The most common of
inherited cystic disease
 It occurs worldwide and in
all race
 Prevalence 1:400 – 1:1000
 Male/Female 1.2 – 1.3
 More progressive in men
than in women
Genetics of ADPKD
 La malattia è dovuta a
mutazioni di almeno 2 geni
 PKD1 – braccio corto del
cromosoma 16 (16p13.3) –
85% circa dei casi
sintomatici
 PKD2 – braccio lungo del
cromosoma 4 (4q21)
(lungo=q, corto=p)
Genetics of ADPKD


PKD1 encode polycystin -1 (PC1)
PKD2 encode polycystin -2 (PC2)

PC1 and PC2 constitute a subfamily of
proteins of Transient Receptor Potential
channels (TRP)

PC2 (or TRPP2) exhibit structural and
functional characteristics of TRP
channel. 6 transmembrane domains.

PC1 (TRPP1) is a distant TRP homolog in
final COOH region. 11 transmembrane
domains.
Protein Produts of PKD genes
Polycystin-1
 Broad tissue expression:
(immunolocalization)
– Kidney (lateral membrane
of tubular cells)
– Brain
– Heart
– Bone
– Muscle
Polycystin-2
 Broad tissue expression:
(immunolocalization)
– Kidney (all nephron
segments)
– Heart
– Ovary
– Testis
– Vascular smooth muscle
– Small intestine
 PKD1 IS MORE SEVERE THAN PKD2
ASSOCIATED DISEASE
 Age at ESRD:




PKD1 54.3 years
PKD2 74
years
Development of cysts: PKD1 more cysts at an early age
Not to faster cyst growth
PKD1 and 2 can be associated with severe
polycistic liver disease
Prevalence of PKD2 associated disease (10-15 %) has likely been
underestimated in clinical study
In population-based study PKD2 reveal higher relative frequencies
(36-29 %)
PKD1 and PKD2 mutations are highly variable and usually private
 Autosomal Dominant Polycystic Kidney Disease: Mutation
Database – PKD foundation (16-3-2015)
 PKD1 mutations:
– 2322 mutazioni elencate nel database, classificate come
certamente patogenetiche, patogenetiche con elevata
probabilità, probabilmente patogenetiche, indeterminate e
probabilmente non patogenetiche
 PKD2 mutations:
– 278 mutazioni elencate nel database
– http://pkdb.mayo.edu/
ADPKD
mutazioni a carico del
gene PKD1
mutazioni a carico del
gene PKD2
proteine tronche e
quindi inattive,
specifiche per ciascuna
mutazione (e quindi per
ciascuna famiglia).
proteine tronche e
quindi inattive,
specifiche per ciascuna
mutazione (e quindi per
ciascuna famiglia).
PATOGENESI
inversione
della polarità
DIAGNOSI
1)Paziente con malattia conclamata (reni di
grandi dimensioni, policistici, ipertensione,
riduzione della funzione renale)
2)Diagnosi precoce nel paziente a rischio
3)Diagnosi prenatale/preimpianto
Renal ultrasound
 Commonly used because of cost and safety.
Revised ultrasound criteria improve the diagnostic performance
 The presence of at least 3 (unilateral or bilateral) renal cysts in at-risk
individuals aged 15–39 years
 2 cysts in each kidney in at-risk 40–59 years
 4 or more cysts in each kidney for at-risk individuals aged 60 years



3 or more cysts (unilateral or bilateral) has a positive predictive value of 100% in the
younger age group and minimizes false-positive diagnoses
2.1 and 0.7% of the genetically unaffected individuals younger than 30 years have one
and two renal cysts, respectively.
In the 30–39 years old, both the original (2 cysts in each kidney) and the revised (>3
cysts, unilateral or bilateral) criteria have a positive predictive value of 100%.
Genetic testing
 Limitations either by linkage or mutation analysis.
 Linkage analysis requires accurate diagnosis, availability
and willingness of sufficient affected family members to
be tested and is feasible in fewer than 50% of families.
 De novo mutation can also complicate interpretation of
results.
 Molecular testing by direct DNA sequencing is now
possible with likely mutations identified in 90% of
patients.
 However, as most mutations are unique and up to onethird of PKD1 changes are missense, the pathogenicity
of some changes is difficult to prove.
Clinica
Liver
Others
Kidneys
ADPKD
Cerebral
arteries
Intestines
Heart
Enlargement of renal cysts and
chronic renal failure.
 Total kidney volume and cyst volumes increased exponentially.
 Mean increase over 3 years was 5.27% per year.
 The rates of change of total kidney and total cyst volumes, and of
the right and left kidney volumes, were strongly correlated.
 Baseline total kidney volume predicted the subsequent rate of
increase in renal volume. GFR declines in patients with baseline
total kidney volume above 1500 ml.
CRISP Study: 241 pts. ; eGFR 60 ml/min; followed prospectively with yearly MR examinations.
Confirmed by European study
Renal manifestations
1
Hypertension
60-100%
2
Kidney failure
50% by age 50
3
Gross ematuria
50 %
4
Infection
common
5
Kidney stones
20-25 %
Ipertensione
Precoce (5% bambini, 40% giovani con funzione renale
norma, 89% ESRD)
Severa (rapida insorgenza di LVH)
Sodio-sensibile - non dipper
Aumenta l’incidenza di complicanze cardiovascolari
Aumenta il rischio di emorragia subaracnoidea
Trattamento (in mancanza di studi controllati):
Target pressorio < 125/75 mmHg
Farmaco di prima scelta: un ACE-inibitore o un sartanico
(finché non controindicato per l’iperkaliemia)
Praticamente sempre necessaria una terapia di associazione
(spesso 3 o più farmaci) e l’uso di ipotensivi potenti
_____________________________
Cyst complications
_________________________________
1 Hypertension
2 Kidney failure
3 Gross ematuria
4 Infection
5 Kidney stones
Renal cyst rupture
Clinical presentation:
1. Acute colicky pain
2. Gross hematuria (Approximately 42% to greater
than 50% of ADPKD patients)
A. self-limited,
B. lasting for 2–7 day
Causative factors for gross hematuria:
1. UTI (most frequent especially among women )
2. Sports
3. abdominal surgeries
4. kidney stones
5. cyst ruptures
 Earlier onset of bleeding (ie, younger
than 30 years), and more frequent
episodes may indicate a risk of
worsening renal function (Johnson and
Gabow 1997) .
 The incidence of gross hematuria is
related to both kidney size and
hypertension (Gabow et al 1992).
Treatment





Bed rest
Hydration
Analgesic administration
NSAIDs should be limited
Nephrectomy or renal arterial
embolization (hematuria so serious and
persistent)
Infected renal cysts
Symptoms:
• Fever
• Flank pain (not radiate and is not relieved
by positioning)
 Laboratory findings:
• Urinalysis and cultures may be negative
with cyst infection
• Blood cultures are positive in most of the
cases
Imaging methods for diagnosis:
 Contrast enhanced CT
 MRI
 Scintigraphy with 111-indium
labeled leukocytes
Treatment
Lipophilic agents such as :
1.
2.
3.
4.
5.
6.
Clindamycin
Ciprofloxacin
Norfloxacin
Trimethoprim- sulfamethoxazole
Therapy should continued for 6 weeks
Cyst drainage in resistant cases
Kidney stones
 The
prevalence in ADPKD adult patients ranges
from 20% to 36%
 20 to 28% of these patients are symptomatic
 Presentations of nephrolithiasis in ADPKD:
1. Flank pain
2. Hematuria
3. UTI
 The most common renal stones in ADPKD are
uric acid stones (50%), which is a much higher incidence
compared to the general population
Pathophysiology:
1.
Metabolic defects (Hypocitraturia occurring in approximately 60% and 49% of ADPKD patients with and
without stones respectively).
2.
Urinary stasis within structural abnormalities due to cyst compression (more stone-forming, higher cyst
numbers).
Kidney failure
In most patients, renal function is maintained within the
normal range, despite relentless growth of cysts, until the
fourth to sixth decade of life.
By the time renal function starts declining, the kidneys
usually are markedly enlarged and distorted with little
recognizable parenchyma on imaging studies.
At this stage, the average rate of GFR decline is 4.4–
5.9 ml/min/year.
Fattori determinano più rapidamente
la perdita della funzione renale
Immodificabili:
Sesso maschile, enia afro-americana
Modificabili: Ipertensione, ematuria, infezioni
delle vie urinarie (forse nell’uomo), gravidanze (?)
ADPKD - Chronic pain
Cyst formation and progressive kidney
enlargement may cause a dull, chronic pain.
The source of mechanical back pain:
 Larger renal volumes (traction of the
renal capsule)
 hypertrophic lumbosacral muscle groups
ADPKD Acute abdominal pain
CAUSE
FREQUENCY
Kidney
Cyst Bleending
++++
Stone
++
Infection
+
Infection
rare
Liver
Cyst Bleending
very rare
Cerebral
aneurysms
Hepatic
and
pancreatic
cysts
Malformations
of selected
vasculature,
Cystis in
other organs
Extraren
Complicanze
al
complicat
extrarenali
ions
Abdominal
wall and
inguinal
hernia
Cardiac
valve
disease
Colonic
diverticula diverticulitis
Hepatic cysts
Prevalence
Female : range from 58%–75%
Male: from 42 to 62%.
Hepatic cyst volume is larger in women
than in men.
Despite the progressive nature of
the cystic disease, the hepatic
parenchyma retains its normal
pattern and function
Complicanze
Tutte estremamente
rare ad eccezione delle
delle cisti asintomatiche
(80 – 90% dei casi) e
del reflusso gastroesofageo
Polycystic liver disease
 Associated with both PKD1 and non-PKD1 genotypes.
 Also occurs as a genetically distinct disease in the
absence of renal cysts.
 Similar to ADPKD, ADPLD is genetically heterogeneous,
with two genes identified (PRKCSH and SEC63)
accounting for approximately one-third of isolated
ADPLD cases.
Cystis in other organs
 Seminal vesicles 40–60% (males)
– Sperm abnormalities and defective motility (asthenozoospermia
or <50% of spermatozoa with forward motility) are common in
ADPKD and rarely may be a cause of male infertility
 Pancreas 5 %
 Arachnoid 8% of patients
 Epididymal and prostate cysts may also
occur with increased frequency
Intracranial aneurysms
 In the general population the estimated
prevalence of ICAs derived from autopsy studies
is 1%–5%.
 In contrast ICAs are seen in approximately 4%–
11.7% of ADPKD patients.
 The risk of subarachnoid hemorrhage (SAH) is
approximately fivefold higher in ADPKD patients.
 In the general population, the incidence of SAH
resulting from a ruptured ICA is about 0.05% per
year
Aneurysmal bleeding in ADPKD patients
tends to occur at a younger age with a
mean age of 35–45 years.
RICAs are responsible for approximately
80% of SAH’s.
The mortality rate within 30 days after
bleeding is almost 45%.
 About 25% of ADPKD patients with a
previous ICA developed a new ICA over a
mean period of 11.4 years
Il rischio di aneurismi cerebrali e della loro
rottura dipende da particolari mutazioni ed
ha quindi base familiare.
Screening (angio-RM):
a) Nei pazienti con storia familiare
b) Nella valutazione pretrapianto
Other vascular manifestations
 Thrombosis of arterovenous fistula (?)
 Thoracic aortic and cervicocephalic
artery dissections
 Coronary artery aneurysms.
 Valvular heart disease
– mitral valve prolapse (26%)
– aortic insufficiency occurs with increased frequency
– Other valves.
They are caused by alterations in the vasculature directly linked to mutations
in PKD1 or PKD2.
Other manifestations
 Colonic diverticulosis and diverticulitis are more
common in ESRD patients with ADPKD than in those
with other renal diseases.
 Extracolonic diverticular disease.
 A rarely reported association of ADPKD is with
idiopathic hypertrophic pyloric stenosis
 Bronchiectasis are detected by CT three times more
frequently in ADPKD compared with control individuals
(37 vs 13%, P<0.002).
TREATMENT
 Blood pressure
 Renal failure
 Chronic pain
 Novel Therapy
NOVEL THERAPIES
Attivi sulla proliferazione dell’epitelio cistico
 inibitori di mTOR (sirolimus, everolimus)
Attivi sul trasporto di acqua dall’interstizio al lume delle cisti AMPc dipendente
 inibitori del recettore V2 dell’ADH (vaptani)
 somatostatina ed analoghi (octreotide)