Cystic Disease of the Kidney

Seth Goldberg

Polycystic Kidney Disease

General Principles

Classification

Polycystic kidney disease has two well-defined autosomal dominant forms (autosomal dominant polycystic kidney disease 1 [ADPKD1] and ADPKD2) as well as one with an autosomal recessive inheritance pattern (ARPKD).
ARPKD leads to renal failure in childhood and adolescence, while both ADPKD forms can remain asymptomatic for several decades into adulthood before renal dysfunction is evident.

Epidemiology

ADPKD has an incidence of 1 in 400 to 1000 live births, with no racial or gender predilection; 85% have a defect in the PKD1 gene (chromosome 16), whereas 15% have a defect at the PKD2 locus (chromosome 4).
ARPKD has an incidence of 1 in 10,000 to 40,000 live births, with the mutation on the PKHD1 gene on chromosome 6.

Pathophysiology

The gene products of PKD1 (polycystin-1) and PKD2 (polycystin-2) localize to the primary cilium of the epithelial cell of the renal tubule, the hepatic bile duct, and pancreatic duct, and to various other tissues in the body.
These gene products are thought to play a role in flow-mediated mechanosensation as well as cell–cell interactions, and defects lead to abnormal epithelial cell proliferation.
In ADPKD, vasopressin signaling may be impaired and affected cells show an abnormal response to increases in cyclic adenosine monophosphate (cAMP), exhibiting a proliferative phenotype.
Only a small percentage of tubules develop cysts, suggesting that a “second-hit” somatic mutation to the normal allele is required to initiate cystogenesis.
As the cysts enlarge, they become separated from the rest of the collecting system; events occurring within the cyst (such as hemorrhage or infection) may not be evident in the urine.
Enlarging cysts may impinge upon the blood flow to normal filtration units, leading to resistant hypertension and interstitial fibrosis.

Diagnosis

Clinical Presentation

Diagnosis is often delayed because the disease is asymptomatic until late in the course.
It is frequently discovered on abdominal imaging performed for an alternate indication; ADPKD-specific reasons for ultrasonography include unexplained early-onset
hypertension, elevated creatinine, or pain from an expanding cyst, cyst hemorrhage, or cyst infection.

History

The history should include an in-depth family history, including relatives who may have required dialysis or a transplant and the age that they reached end-stage renal disease.
Family history of cerebral aneurysms or sudden death of unknown etiology must be ascertained, as this would put the patient at risk for a similar event and necessitate screening.
A personal history of headaches or neurologic symptoms must be sought.
Flank and abdominal pain may be suggestive of symptomatic renal or hepatic cysts.
A history of hematuria, dysuria, and nephrolithiasis should be investigated.
Caffeine intake should be quantified.
In women, the history of estrogen exposure (pregnancy, contraception, hormone replacement therapy) should be assessed.

Physical Examination

The physical examination is often normal in the early stages of ADPKD.
The first presenting sign of an underlying problem is frequently early-onset hypertension.
As the kidneys progressively enlarge, the cysts may be palpable on abdominal examination.
Hepatic cysts may also be palpable and elicit epigastric tenderness.
Cardiac auscultation may reveal the mid-systolic click of mitral valve prolapse.

Diagnostic Criteria

The diagnosis of ADPKD is made using the combination of renal cysts, family history, and the constellation of extrarenal manifestations.
Ultrasound diagnostic criteria have been established for patients at-risk for ADPKD (those with an affected parent); however, the absence of cysts in a patient under the age of 40 does not rule out the disease.¹ Please see Table 14-1.
As computed tomography (CT) scans or magnetic resonance imaging (MRI) can detect smaller cysts, the conventional diagnostic criteria do not apply to these modalities and no guidelines have been validated.
Genetic testing is available for both forms of ADPKD, with use primarily in young patients contemplating living kidney donation to an affected family member in order to rule out subclinical disease. The accuracy of the test depends on identifying the specific mutation (which differs between families) and so the utility of the genetic test is limited in patients with few or no affected relatives.
For children of an affected parent, it is appropriate to wait until the children are 18 years old to decide for themselves if they want to undergo testing. A diagnosis may make it more difficult to obtain health or life insurance but could allow for the option of disease-modifying therapy approved for adults.
It is prudent for at-risk relatives to obtain regular blood pressure checks, and to pursue further evaluation if indicated.

TABLE 14-1 ULTRASOUND CRITERIA FOR DIAGNOSIS OF ADPKD

Age	Number of Cysts Required in At-Risk Individual
15–39	At least three cysts between both kidneys
40–59	At least two cysts in each kidney
≥60	At least four cysts in each kidney

Differential Diagnosis

The diagnosis of ADPKD is not difficult when there is an established family history of disease; when absent, the possibility of an alternative renal cystic disease must be excluded.
Acquired cystic disease in the presence of renal dysfunction typically exhibits small, shrunken kidneys.
The cysts in medullary cystic kidney disease (MCKD) are often a late manifestation, with small-to-normal–sized smooth-contoured kidneys and cysts confined to the corticomedullary junction or renal medulla.
Medullary sponge kidney (MSK) can also be distinguished from ADPKD by the medullary location of the cysts and collecting duct dilation.
Solid renal nodules are uncommon in ADPKD, but may be seen in tuberous sclerosis and von Hippel–Lindau (VHL) syndrome.
The presence of extrarenal manifestations, such as hepatic cysts, can be a helpful clue to make the diagnosis of ADPKD.

Treatment

In 2018, the vasopressin antagonist tolvaptan was approved in the United States to delay progression of ADPKD. Patients with ADPKD complicated by hypertension, progressive decline in renal function (but with a glomerular filtration rate >25 mL/min/1.73 m²), or kidney lengths >16.5 cm are potential candidates for treatment. Given the risk of liver toxicity, drug prescribing is tightly regulated and requires the frequent monitoring of liver enzymes (baseline, 2 weeks, 4 weeks, every 4 weeks for 18 months, then every 3 months afterwards). Common side effects include polyuria, nocturia, and increased thirst, which may be overwhelming for some patients and thus potential treatment subjects should be counseled on this possibility, while being instructed to maintain at least 2 to 4 L of fluid intake daily. It is generally recommend to discontinue diuretics prior to initiating tolvaptan.²^,³
Blood pressure control remains an important cornerstone of treatment.
Anemia is not often an early problem for these patients, as compared to other causes of chronic kidney disease, given the production of erythropoietin by cells surrounding the cysts.
Caffeine intake should be reduced or avoided, given the theoretical risk of increasing cAMP levels and thus cyst growth; animal models and human studies have not confirmed this risk.
Large-volume surgical cyst reduction does not affect long-term renal outcomes, although select aspiration and sclerosis of severely symptomatic renal or hepatic cysts can provide relief.

Complications

Renal Manifestations

Hematuria is a common finding in patients with ADPKD and may represent a ruptured cyst, a cyst infection, or nephrolithiasis.
Cyst hemorrhage is self-limited, lasting from several days to 1 to 2 weeks and can be very painful; as cysts may have become separated from the rest of the urinary tract, hematuria is not always present. Cyst hemorrhage is treated conservatively with oral hydration, bed rest, and analgesia.
Cyst infection may present with fever, dysuria, pyuria, and flank pain; however, as with cyst hemorrhage, there may not be direct communication with the remainder of the urinary tract and so dysuria may be absent and the urine culture may be negative.
Treatment of cyst infection should include an antibiotic with good cyst penetration (ciprofloxacin, sulfamethoxazole–trimethoprim) for 3 to 4 weeks.
Nephrolithiasis can occur in patients with ADPKD, with an increased frequency of uric acid stones as compared to the general population. Calcium-based stones are also common in this group. Management would be the same as for patients without ADPKD.
Hypertension in this population is thought to be mediated, at least partially, through activation of the renin–angiotensin–aldosterone axis through local ischemia from external compression by enlarging cysts. The onset of hypertension is common before the age of 35, despite preserved renal filtration.
A concentrating defect is generally mild and may be seen early in the disease course; this may be accounted for by vasopressin receptor (V₂) signaling abnormalities.

Extrarenal Manifestations

Liver cysts are common and are present in up to 80% of patients with ADPKD. Progression to liver dysfunction, however, is rare.
- Liver enlargement may lead to abdominal fullness, discomfort, or early satiety. In unusual circumstances, the pain may be severe enough as to prompt cyst drainage with sclerosis or surgical unroofing of the culprit lesion.
- Liver cysts are more common in women with increased estrogen exposure.
Cerebral aneurysms constitute the most serious extrarenal manifestation and are found to cluster within families with certain mutations.
- When there is a family history of a cerebral aneurysm or sudden death of unknown cause, the incidence is increased to 20%. In the absence of such a family history, the risk is no greater than in the general population (1% to 2%).
- The risk of aneurysm rupture is greater in patients with uncontrolled hypertension.
- Patients with neurologic symptoms or those with a family history of cerebral aneurysms should undergo magnetic resonance angiography testing. Others who should be screened include patients with high-risk occupations in which loss of consciousness would put others at risk (such as commercial pilots), patients needing anticoagulation, or those undergoing a surgical intervention with potential hemodynamic instability.
- Referral to neurosurgery is recommended when an aneurysm is discovered; smaller aneurysms (<5 to 7 mm) are typically followed serially, while those that are at higher risk of rupture should undergo repair.
- For patients at increased risk for cerebral aneurysms but with negative scans, reimaging within 10 years should be performed to detect new lesions.
Colonic diverticulosis occurs with greater frequency in patients with ADPKD with a higher risk of perforation compared to the general population.
Cardiac valvular disease, particularly mitral valve prolapse, is common in ADPKD patients. Most patients are asymptomatic, although some patients may report palpitations.
Abdominal wall hernias occur with increased frequency, and may worsen if peritoneal dialysis is pursued in these patients without surgical correction.