DOENCA RENAL POLICISTICA AUTOSSOMICA DOMINANTE

Question 1

Autosomal-Dominant Polycystic Kidney Disease

Epidemiology

DOENÇA RENAL MONOGENICA MAIS COMUM

QUARTA CAUSA DE ESKD NOS EUA

autossomica dominante e ter o gene quase que significa ter a doença = alta penetrancia

Answer 1

Incidence estimated to be 1 in 500 to 1,000 live births.

ADPKD affects 12.5 million people worldwide, both genders, and all ethnic groups equally.

10% of patients with ESRD and fourth leading cause for renal replacement therapy worldwide.

Implicating factors involved in cystogenesis and growth include reduction in intracellular calcium, increased intracellular cAMP, increased epithelial chloride fluid secretion via cystifc fibrosis transmembrane conductance regulator channels, and increased epithelial cellular proliferation.

Renal cysts are thought to develop from a “two-hit” mechanism:

First “hit”: full or partial loss of functional polycystin

AND

Second “hit”: Somatic inactivation of normal allele

Question 2

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 2

PKD1 and PKD2 encode for polycystin (PC) 1 and 2, respectively. PC1 and PC2 form a polycystin complex on primary cilium on the apical surface of renal tubular and biliary epithelial cells que functions as a mechanosensor that regulates flow-mediated calcium entry into cells, which in turn triggers calcium release from the ER into the cytoplasm (this is known as “calcium-induced calcium release”).

Mutations of PC1, PC2 lead to altered intracellular calcium homeostasis. The reduced intracellular calcium level enhances accumulation of cAMP, an important mediator of cystic growth. cAMP accumulation occurs via increased adenylyl cyclase activity and possibly decreased phosphodiesterase I activity.

Question 3

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 3

PC1 on the cell surface also interacts with tuberin. A disrupted tuberin–PC1 interaction is thought to cause a loss of downstream inhibition of the mTOR. Activation of mTOR leads to increased protein synthesis and cell proliferation.

Family history may be absent in 10% to 15% of patients with ADPKD due to de novo mutations, mosaicism, mild disease from PKD2, nontruncating PKD1 mutations, or misdiagnosis.

Despite large-sized kidneys, ADPKD cysts only involve <1% to 2% of all nephrons.

Question 4

Autosomal-Dominant Polycystic Kidney Disease

Answer 4

Epidemiology
Relative frequencies of PKD1 and PKD2 are 65% to 70% and 25% to 30%, respectively.

obs: se uma familia pelo menos um caso de alguem que entrou em dialise antes dos 55 anos = PKD1 100%

se tiver um familiar que nao entrou em dialise até os 70 anos = pkd2

Question 5

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 5

Clinical Manifestations
PKD1 have more cysts and larger kidneys compared with PKD2.

Cystic growth rates are similar between PKD1 and PKD2.

The lower number of cysts, a.k.a. “lower cyst dose,” in PKD2 is thought to result in later development of ESRD in PKD2 compared with PKD1.

Question 6

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Clinical findings from the consortium for radiologic imaging studies of PCKD (CRISP):

Answer 6

Clinical findings from the consortium for radiologic imaging studies of PCKD (CRISP):

The value of MRI in the study of PCKD:

Cyst volume increase may be detected within 6 months

Renal blood flow may be used as a marker of disease severity. The decline in kidney function and disease progression of ADPKD appears to be closely linked with the decline in renal blood flow.

Question 7

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Clinical findings from the consortium for radiologic imaging studies of PCKD (CRISP):

Answer 7

PKD1 is a more severe disease compared to PKD2 because in PKD1 more cysts develop earlier, not grow faster.

acometimento renal=

formacao de multiplos cistos= cistos simples acomete cortex e medula

aumento do volume renal

has, hematuria, dor lombar, infeccao dos cistos,

litiase >30%

drc e drc terminal

Question 8

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 8

Ultrasound diagnostic criteria for PKD1, PKD2, and unknown genotype:

At-risk individuals age 15 to 39 years: three or more cysts unilateral or bilateral

40 to 59 years: two or more cysts in each kidney

>60 years: more than four cysts in each kidney

NOTE: Diagnosis in children is controversial. In the United States, presymptomatic screening for at-risk children is currently not recommended.

Question 9

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 9

MRI-based criteria for disease exclusion in at-risk individuals and below age 40: “the finding of fewer than 5 renal cysts by MRI is sufficient for disease exclusion.” - KDIGO 2015.

However, for kidney donors at risk for PCKD (positive family history) and age < 40 years or have in utero presentation or unilateral disease, direct mutation analysis for PKD1 and PKD2 is warranted.

Preimplantation genetic diagnosis is available for ADPKD.

Question 10

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Risks for progression:

Answer 10

Patients with TKV > 600 mL per meter of patient height or kidney length > 17 cm likely progress to stage 3 CKD within 8 years.

TKV/height = sum of [kidney length × width × depth (cm) × π/6] of both kidneys/height (m),

relacao de volume renal com a altura do paciente para estimar progressao da doença

1A E 1B =melhor prognostico

1C 1d 1 e PIOR PROGNOSTICOS

Question 11

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Risks for progression:

Answer 11

GENE PKD1

mayo 1c 1e

sintomas antes dos 30 anos

Urine albumin excretion

HTN (particularly if onset prior to age 35)

Male gender

Question 12

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Stones:

Answer 12

Cyst burden (high TKV) is associated with hematuria and nephrolithiasis.

calculo=20-35% dos pacs adultos=Uric acid stones are most common and less commonly, calcium oxalate.

Increased stone risk is thought to be due to urinary stasis from cyst compression, reduced urinary citrate excretion, low urinary pH presumably due to defective ammonium excretion, hypercalciuria, and hyperuicosuria.

Occurs even prior to reduction in GFR in 60% of patients, thought to be due to RAAS activation from cyst expansion into renal parenchyma

Absence of nocturnal BP dipping (40% of patients)

Question 13

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

HTN:

Answer 13

Occurs even prior to reduction in GFR in 60% of patients, thought to be due to RAAS activation from cyst expansion into renal parenchyma

Absence of nocturnal BP dipping (40% of patients)

Question 14

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 14

Left ventricular hypertrophy (even in normotensive patients, up to 25%)

Pain (back, abdomen, head, chest, legs)

resumo

cistos hepaticos 80%

aneurismas intra cranianos 20-30%

prolapso de valv mitral 25%

diverticulos =eskd20%

aneurisma de aorta

bronquiectasias 35%

Question 15

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Cyst infections:

Answer 15

Most common: E. coli; treat with fluoroquinolones or trimethoprim–sulfamethoxazole for better cystic penetration for 4 to 8 weeks, up to 3 months; vancomycin or erythromycin if streptococcal or staphylococcal infection, metronidazole or clindamycin if anaerobic organisms; drainage or surgical intervention may be necessary.

18-fluorodexoyglucose-positron emission tomography may be considered to identify infected cyst.

Question 16

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 16

RCC: recent retrospective study revealed 5% malignant neoplasms with elective nephrectomy in patients with ADPKD. The incidence of clinically significant RCC in those with ESRD is not increased compared with that of other kidney diseases. Detection of RCC may be improved with MRI with and without gadolinium.

Question 17

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 17

Polycystic liver disease occurs in >85% of patients by age 25 to 34 and 94% by age 35 to 46 (CRISP study).

Liver function is often preserved, but can be complicated with transaminitis, cyst infections, and hepatic venous outflow obstruction (Budd Chiari). Progressive disease may be seen with pregnancies, oral contraceptives, and hormonal replacement therapy.

Question 18

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Cerebral aneurysms (most often in the anterior circulation of circle of Willis):

Answer 18

Asymptomatic cerebral aneurysms may be detected in 5% of patients without a family history and up to 20% in those with a family history.

High risk of rupture for aneurysms > 10 mm in diameter.

Screening indications: family history of aneurysm, previous known aneurysms, high-risk occupations (e.g., pilots), kidney transplantation, pregnancy, elective surgery. Screening recommendations apply to those with good life expectancy

historia familiar de aneurisma ou morte subita, antecedente pessoal, procedimento cirurgico, indicacao aco, ocupacao de risco, sinais de alerta, ansiedade

Question 19

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Cerebral aneurysms (most often in the anterior circulation of circle of Willis):

Answer 19

Screening indications: family history of aneurysm, previous known aneurysms, high-risk occupations (e.g., pilots), kidney transplantation, pregnancy, elective surgery. Screening recommendations apply to those with good life expectancy

historia familiar de aneurisma ou morte subita, antecedente pessoal, procedimento cirurgico, indicacao aco, ocupacao de risco, sinais de alerta, ansiedade

Question 20

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 20

Other associations: cardiac valve abnormalities (mitral valve prolapse, aortic. mitral, tricuspid regurgitation), pericardial effusions, asymptomatic bronchiectasis, inguinal/umbilical hernia (may be problematic with peritoneal dialysis), diverticulosis (increased risk of perforation in kidney transplant recipients)

Question 21

Autosomal-Dominant Polycystic Kidney Disease

Management

Dietary:

Answer 21

Salt restriction 2 to 3 g/d (increased urinary sodium correlates with increased TKV over time)

Minimize caffeine intake (caffeine is a methylxanthine that increases intracellular cAMP levels in cultured renal epithelial cells which could potentially accelerate cystic growth).

Question 22

Autosomal-Dominant Polycystic Kidney Disease

Management

Dietary:

Answer 22

Adequate free water intake to minimize ADH secretion (goal urine osmolality ~250 mOsm/kg with caution not to cause hyponatremia. Note, however, although this practice is commonly practiced, its benefit has not been proven)

Question 23

Autosomal-Dominant Polycystic Kidney Disease

Management

Control HTN:

Answer 23

HAS é um fato de progressao ruim logo tem que controlar a pressao

RAAS inhibitors are first-line BP-lowering agents in combination with lifestyle modification and sodium-restricted diet.

associacao com BCC

evitar diureticos =desidratacao estimula o AMP c

meta= 120x80, jovens 110x75 tfg>60

Question 24

Autosomal-Dominant Polycystic Kidney Disease

Management

Control HTN:

Answer 24

HALT-PKD (60-month follow up for TKV, 96-month for eGFR decline):

ACEI alone can adequately control HTN in most patients. The addition of ARB did not provide any additional benefits.

Question 25

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 25

5-year survival of ADPKD patients undergoing hemodialysis is superior to those with other kidney diseases.

Question 26

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 26

Compared with arteriovenous grafts and fistulas, the use of catheters for HD in ADPKD is associated with an increased risk for renal and liver cyst infections.

Question 27

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 27

Peritoneal dialysis is not contraindicated. However, there is a higher risk of abdominal wall hernia. Overall survival rate and peritonitis rates are similar to those seen in nondiabetic PD patients.

Question 28

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 28

ADPKD patients have been reported to have higher hemoglobin levels and lower requirement for erythropoiesis stimulating agents.

Question 29

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 29

Kidney transplantation:

Deceased ADPKD kidneys with good function and relatively small size may still be considered for recipients who consent.

Noted post-transplant complications: GI complications (e.g., perforation from diverticulosis), erythrocytosis, urinary tract infections, thromboembolic complications

Question 30

Autosomal-Dominant Polycystic Kidney Disease

Management

Direct medical therapies of ADPKD:

Answer 30

ADH (vasopressin) V2 receptor antagonists (tolvaptan): Tolvaptan has been shown to slow down TKV rate of growth and eGFR decline rate. Renal toxicity and other adverse effects (transaminitis=hepatite medicamentosa) are of great concerns currently. (Tolvaptan in patients with ADPKD: TEMPO study)

Question 31

Autosomal-Dominant Polycystic Kidney Disease

Management

Direct medical therapies of ADPKD:

Answer 31

Increased signaling of the mTOR complex 1 is thought to enhance cystic growth in ADPKD. Two clinical studies involving sirolimus, however, have not shown benefits in TKV or kidney function at 18-month follow-up. Notably, urine albumin to creatinine ratio was higher in the sirolimus group. (Sirolimus for ADPKD [SUISSE] study)

Question 32

Autosomal-Dominant Polycystic Kidney Disease

Management

Direct medical therapies of ADPKD:

Answer 32

Everolimus (mTOR inhibitor): slowed TKV increase but no slowing of eGFR decline detected over a 2-year study period

Question 33

Autosomal-Dominant Polycystic Kidney Disease

Management

Direct medical therapies of ADPKD:

Answer 33

HMG-CoA reductase inhibitor (statin): The use of pravastatin in children treated with ACEI revealed slower rates of TKV growth and reduced rate of GFR decline.

Question 34

Autosomal-Dominant Polycystic Kidney Disease

Management

Management of ADPKD associated complications:

Answer 34

Pain:

Sequential approach based on the World Health Organization’s pain relief ladder is recommended.

Others: celiac plexus blockade, radiofrequency ablation, spinal cord stimulation, laparoscopic or percutaneous transluminal catheter-based denervation

Question 35

Autosomal-Dominant Polycystic Kidney Disease

Management

Management of ADPKD associated complications:

Answer 35

Gross hematuria:

Observation, hospitalization if severe, fluid support as needed

Prolonged hematuria (i.e., >7 days) dictates further evaluation for neoplasm.

Question 36

Autosomal-Dominant Polycystic Kidney Disease

Management

Management of ADPKD associated complications:

Answer 36

Polycystic liver disease:

For severe polycystic liver disease, aspiration, sclerotherapy, fenestration, partial or segmental liver resection, or liver transplantation may be considered.

Question 37

Autosomal-Dominant Polycystic Kidney Disease

Management

Management of ADPKD associated complications:

Answer 37

Somatostatin analogs use is restricted to clinical trials or compassionate use.

Cyst infections are best treated with percutaneous drainage and prolonged therapy with fluoroquinolones.

Question 38

Autosomal-Dominant Polycystic Kidney Disease

Management

Pregnancy:

Answer 38

Increased risk for progression of liver cysts

Increased risk for pregnancy-induced HTN and preeclampsia

Multiple pregnancies (>3) are associated with a greater risk for GFR decline.

Question 39

criterios de PEI

Answer 39

15-39 anos → 3 ou + cistos uni ou bilateral

40-59 anos→ 2 ou mais cistos em cada rim

>60 anos → 4+ cistos em cada rim

>40 anos com menos de 2 cistos = EXCLUSAO

Caso indice= 16-40 anos se mais de 10 cistos em ambos os rins na rnm

exclusao 16-40 anos e menos de 5 cistos em ambos os rins na rnm

Question 40

indicacao do teste genetico

Answer 40

candidato a doacao de rim com historia familiar + que nao preenche criterios de exclusao (ainda nao completou 40 anos)

casos inconclusivos

apresentacao atipica da doença

variabilidade intra familiar

caso novo- ausencia de historico familiar

Question 41

tratamento

Answer 41

reducao da pa

inibicao da producao do ampc=

ingestao hidrica elevada= inibir adh 3-4 litros

osm urinaria <250

cuidado nos paciente com drc, uso de tiazidicos e siadh

restricao de cafeina

LDL <100