AutosomalAutosomal Dominant Polycystic Kidney Disease Dominant Polycystic Kidney Disease (ADPKD)(ADPKD)

((Malattia policistica autosomica dominante o dell’adulto)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 ADPKDGenetics of ADPKD

La malattia è dovuta a La malattia è dovuta a mutazioni di almeno 2 mutazioni di almeno 2 genigeni

PKD1 – braccio corto del PKD1 – braccio corto del cromosoma 16 (16p13.3) cromosoma 16 (16p13.3) – 85% circa dei casi – 85% circa dei casi sintomaticisintomatici

PKD2 – braccio lungo del PKD2 – braccio lungo del cromosoma 4 (4q21)cromosoma 4 (4q21)

(lungo=q, corto=p)

Genetics of ADPKDGenetics of ADPKD PKD1 encode polycystin -1 (PC1)PKD1 encode polycystin -1 (PC1) PKD2 encode polycystin -2 (PC2)PKD2 encode polycystin -2 (PC2)

PC1 and PC2 constitute a subfamily of PC1 and PC2 constitute a subfamily of proteins of Transient Receptor proteins of Transient Receptor Potential channels (TRP)Potential channels (TRP)

PC2 (or TRPP2) exhibit structural and PC2 (or TRPP2) exhibit structural and functional characteristics of TRP functional characteristics of TRP channel. 6 transmembrane domains.channel. 6 transmembrane domains.

PC1 (TRPP1) is a distant TRP homolog PC1 (TRPP1) is a distant TRP homolog in final COOH region. 11 in final COOH region. 11 transmembrane domains.transmembrane domains.

Protein Produts of PKD genes

Polycystin-1Polycystin-1

Broad tissue expression: (immunolocalization)– Kidney (lateral membraneof tubular cells)– Brain– Heart– Bone– Muscle

Polycystin-2Polycystin-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 Autosomal Dominant Polycystic Kidney Disease: Mutation Database – PKD foundation (16-3-2015)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/

PATOGENESI

inversione della polarità

DIAGNOSIDIAGNOSI

1)Paziente con malattia conclamata (reni di grandi dimensioni, policistici, ipertensione, riduzione della funzione renale)

2)Diagnosi precoce nel paziente a rischio3)Diagnosi prenatale/preimpianto

Renal ultrasoundRenal ultrasound

Commonly used because of cost and safety. Commonly used because of cost and safety.

Revised ultrasound criteria improve the diagnostic Revised ultrasound criteria improve the diagnostic performance performance

The presence of at least 3 (unilateral or bilateral) renal cysts The presence of at least 3 (unilateral or bilateral) renal cysts in at-in at-risk individualsrisk individuals aged 15–39 years aged 15–39 years

2 cysts in each kidney in at-risk 40–59 years2 cysts in each kidney in at-risk 40–59 years 4 or more cysts in each kidney for at-risk individuals aged 60 years4 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 3 or more cysts (unilateral or bilateral) has a positive predictive value of 100% in the younger age group and minimizes false-positive diagnosesthe younger age group and minimizes false-positive diagnoses

2.1 and 0.7% of the genetically unaffected individuals younger than 30 years have 2.1 and 0.7% of the genetically unaffected individuals younger than 30 years have one and two renal cysts, respectively. one and two renal cysts, respectively.

In the 30–39 years old, both the original (2 cysts in each kidney) and the revised 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%.(>3 cysts, unilateral or bilateral) criteria have a positive predictive value of 100%.

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 one-third of PKD1 changes are missense, the pathogenicity of some changes is difficult to prove.

Genetic testing

ADPKD

ClinicaClinica

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 %

IpertensioneIpertensione

Precoce (5% bambini, 40% giovani con funzione Precoce (5% bambini, 40% giovani con funzione renale norma, 89% ESRD)renale norma, 89% ESRD) Severa (rapida insorgenza di LVH)Severa (rapida insorgenza di LVH) Sodio-sensibile - non dipperSodio-sensibile - non dipperAumenta l’incidenza di complicanze cardiovascolariAumenta l’incidenza di complicanze cardiovascolariAumenta il rischio di emorragia subaracnoideaAumenta il rischio di emorragia subaracnoideaTrattamento (in mancanza di studi controllati):Trattamento (in mancanza di studi controllati):

Target pressorio Target pressorio << 125/75 mmHg 125/75 mmHgFarmaco di prima scelta: un ACE-inibitore o un sartanico Farmaco di prima scelta: un ACE-inibitore o un sartanico (finché non controindicato per l’iperkaliemia) (finché non controindicato per l’iperkaliemia) Praticamente sempre necessaria una terapia di Praticamente sempre necessaria una terapia di associazione (spesso 3 o più farmaci) e l’uso di ipotensivi associazione (spesso 3 o più farmaci) e l’uso di ipotensivi potenti potenti

1 Hypertension

2 Kidney failure

3 Gross ematuria

4 Infection

5 Kidney stones

_____________________________

Cyst complications_________________________________

Renal cyst rupture

Clinical presentation:1.Acute colicky pain2.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:§ UTI (most frequent especially among women )§ Sports§ abdominal surgeries§ kidney stones§ 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).

TreatmentTreatment

Bed rest Hydration Analgesic administration NSAIDs should be limited Nephrectomy or renal arterial

embolization (hematuria so serious and persistent)

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

Infected renal cysts

Imaging methods for diagnosis:

Contrast enhanced CTMRIScintigraphy with 111-indium

labeled leukocytes

Lipophilic agents such as :

1.Clindamycin2.Ciprofloxacin3.Norfloxacin4.Trimethoprim- sulfamethoxazole5.Therapy should continued for 6 weeks6.Cyst drainage in resistant cases

Treatment

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 pain2.Hematuria3.UTIThe most common renal stones in ADPKD are uric acid stones (50%), which is a much higher incidence compared to the general population

Kidney stones

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 Fattori determinano più rapidamente la perdita della rapidamente la perdita della

funzione renale funzione renale Immodificabili: Immodificabili: Sesso maschile, enia afro-americanaSesso maschile, enia afro-americana

Modificabili: Ipertensione, ematuria, infezioni Modificabili: Ipertensione, ematuria, infezioni delle vie urinarie (forse nell’uomo), delle vie urinarie (forse nell’uomo), gravidanze (?)gravidanze (?)

ADPKD - Chronic painCyst 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 +

Liver

Infection rare

Cyst Bleending very rare

Complicanze extrarenali

Hepatic cystsHepatic 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 estremamenterare ad eccezione delledelle cisti asintomatiche(80 – 90% dei casi) e del reflusso gastro- esofageo

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.

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

Cystis in other organsCystis in other organs

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

Intracranial aneurysms

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

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 vascular 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).

Other manifestations

Blood pressureRenal failureChronic painNovel Therapy

TREATMENTTREATMENT

NOVEL THERAPIES

Attivi sulla proliferazione dell’epitelio cistico inibitori di mTOR (sirolimus, everolimus)

Attivi sul trasporto di acqua dal- l’interstizio al lume delle cisti AMPc dipendente

inibitori del recettore V2 dell’ADH (vaptani) somatostatina ed analoghi (octreotide)