Renal Cystic Disease, Part II

Question 1

Autosomal-Dominant Polycystic Kidney Disease

Epidemiology

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.

Question 2

Autosomal-Dominant Polycystic Kidney Disease

Answer 2

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

Question 3

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 3

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.

Question 4

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 4

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

First “hit”: full or partial loss of functional polycystin (or even overexpression of polycystin in rodents) AND

Second “hit”: Somatic inactivation of normal allele

Question 5

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 5

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.

Question 6

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 6

The PC complex 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”).

Question 7

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 7

PC2 is also present in the ER, where it interacts with inositol triphosphate and ryanodine receptors to signal calcium release into the cytoplasm from intracellular stores.

Question 8

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 8

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 9

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 9

cAMP stimulates chloride-driven fluid secretion into cysts.

While cAMP inhibits cell proliferation under normal conditions, it stimulates cell proliferation in calcium deprived states. The proliferative effect of cAMP may be enhanced by epithelial growth factor (EGF)-like factors present in cyst fluid.

Note that ADH can increase cAMP levels via activation of adenylate cyclase.

Question 10

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 10

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.

Question 11

Autosomal-Dominant Polycystic Kidney Disease

Pathogenesis

Answer 11

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 12

Autosomal-Dominant Polycystic Kidney Disease

Answer 12

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

Disease may manifest in <1% of cases.

Question 13

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 13

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 14

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

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

Answer 14

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

Question 15

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

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

Answer 15

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 16

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

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

Answer 16

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

Question 17

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

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

Answer 17

Cystic growth and increase in total kidney volume (TKV) is a continuous and steady process that is patient specific. At 3-year follow-up, the mean annual growth rate was 5% to 6%.

PKD1 typically reaches ESRD by age 40s and PKD2 by age 60s.

Question 18

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 18

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 19

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 19

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.

Question 20

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 20

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 21

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Risks for progression:

Answer 21

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),

Question 22

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Risks for progression:

Answer 22

Urine albumin excretion

HTN (particularly if onset prior to age 35)

Male gender

Question 23

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Risks for progression:

Answer 23

Low birth weight

Higher plasma copeptin level is associated with higher TKV and urinary albumin excretion and reduced GFR and effective renal blood flow.

Others: sickle cell trait, dyslipidemia

Question 24

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Stones:

Answer 24

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

Uric acid stones are most common and less commonly, calcium oxalate.

Question 25

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Stones:

Answer 25

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.

Question 26

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

HTN:

Answer 26

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 27

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 27

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

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

Question 28

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Cyst infections:

Answer 28

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 29

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 29

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 30

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 30

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 31

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

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

Answer 31

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.

Question 32

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

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

Answer 32

Mutations in the 5’-flanking region of the PKD1 gene are more likely to have cerebral aneurysms compared to those at the 3’-end.

Question 33

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

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

Answer 33

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.

Question 34

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

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

Answer 34

Small unruptured aneurysms require regular follow-up, 6 to 24 months.

Patients with family history and negative screening should be rescreened in 5 to 10 years.

Screening study of choice is time-of-flight MRI without gadolinium.

Question 35

Autosomal-Dominant Polycystic Kidney Disease

Clinical Manifestations

Answer 35

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 36

Autosomal-Dominant Polycystic Kidney Disease

Management

Dietary:

Answer 36

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 37

Autosomal-Dominant Polycystic Kidney Disease

Management

Dietary:

Answer 37

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 38

Autosomal-Dominant Polycystic Kidney Disease

Management

Control HTN:

Answer 38

RAAS inhibitors are first-line BP-lowering agents in combination with lifestyle modification and sodium-restricted diet. Selection of second-line agent is controversial and should be based on patients’ comorbidities.

Question 39

Autosomal-Dominant Polycystic Kidney Disease

Management

Control HTN:

Answer 39

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 40

Autosomal-Dominant Polycystic Kidney Disease

Management

Control HTN:

Answer 40

Lowering BP below goal (target 95-110/60-75 mm Hg) in young patients with good kidney function reduced the annual TKV growth rate (5.6% vs. 6.6%), renal vascular resistance, urine albumin excretion, and left ventricular mass. The rate of decline in eGFR, however, was not significantly different.

Question 41

Autosomal-Dominant Polycystic Kidney Disease

Management

Control HTN:

Answer 41

ACEI or ARB is associated with reducing left ventricular mass index and proteinuria.

Use of diuretics is associated with higher increase in TKV compared to RAAS inhibitors.

There are concerns that CCB may accelerate cystic growth.

Question 42

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 42

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

Question 43

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 43

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 44

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 44

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 45

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 45

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

Question 46

Autosomal-Dominant Polycystic Kidney Disease

Management

ESRD/Renal replacement therapy:

Answer 46

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 47

Autosomal-Dominant Polycystic Kidney Disease

Management

Direct medical therapies of ADPKD:

Answer 47

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) are of great concerns currently. (Tolvaptan in patients with ADPKD: TEMPO study)

Question 48

Autosomal-Dominant Polycystic Kidney Disease

Management

Direct medical therapies of ADPKD:

Answer 48

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 49

Autosomal-Dominant Polycystic Kidney Disease

Management

Direct medical therapies of ADPKD:

Answer 49

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

Question 50

Autosomal-Dominant Polycystic Kidney Disease

Management

Direct medical therapies of ADPKD:

Answer 50

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 51

Autosomal-Dominant Polycystic Kidney Disease

Management

Management of ADPKD associated complications:

Answer 51

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 52

Autosomal-Dominant Polycystic Kidney Disease

Management

Management of ADPKD associated complications:

Answer 52

Gross hematuria:

Observation, hospitalization if severe, fluid support as needed

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

Question 53

Autosomal-Dominant Polycystic Kidney Disease

Management

Management of ADPKD associated complications:

Answer 53

Polycystic liver disease:

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

Question 54

Autosomal-Dominant Polycystic Kidney Disease

Management

Management of ADPKD associated complications:

Answer 54

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 55

Autosomal-Dominant Polycystic Kidney Disease

Management

Pregnancy:

Answer 55

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.