Chapter 70. Polycystic Kidneys

A 43-year-old woman with newly diagnosed hypertension reports persistent bilateral flank pain. She has a family history of “kidney problems.” On urinalysis, she is noted to have microscopic hematuria. An ultrasound and abdominal CT scan show bilateral polycystic kidneys (Figure 70-1).

Polycystic kidney disease (PKD) is a manifestation of a group of inherited disorders resulting in renal cyst development. In the most common form, autosomal-dominant polycystic kidney disease (ADPKD), extensive epithelial-lined cysts develop in the kidney; in some cases, abnormalities also occur in the liver, pancreas, brain, arterial blood vessels, or a combination of these sites.

• Most common tubular disorder of the kidney, affecting 1 in 300 individuals.
• Autosomal dominant in 90% of cases, rarely as an autosomal recessive trait.1
• Sporadic mutation in approximately 1:1000 individuals.
• ADPKD accounts for approximately 5% to 10% of cases of end-stage renal disease (ESRD) in the United States.
• Most frequently seen in the third and fourth decades of life, but can be diagnosed at any age.

• ADPKD results from mutations in either of 2 genes that encode plasma membrane-spanning polycystin 1 (PKD1) and polycystin 2 (PKD2).2 Polycystins regulate tubular and vascular development in the kidneys and other organs (liver, brain, heart, and pancreas). PKD1 and PKD2 are colocalized in primary cilia and appear to mediate Ca2+ signaling as a mechanosensor, essential for maintaining the differentiated state of epithelia lining tubules in the kidney and biliary tract.3 These mutations result in many abnormalities including increased proliferation and apoptosis and loss of differentiation and polarity.4
• Few (1% to 5%) nephrons actually develop cysts.
• Remaining renal parenchyma shows varying degrees of tubular atrophy, interstitial fibrosis, and nephrosclerosis.
• Cysts are also found in other organs such as liver (Figure 70-2), spleen, pancreas, and ovaries. Liver cysts are found in up to 80% of patients with ADPKD.2 There is also an increased incidence of intracranial aneurysms (5% to 12%).
• Autosomal-recessive PKD (ARPKD) is the neonatal form of PKD that is associated with enlarged kidneys and biliary dysgenesis.3 The genetic mutation in PKHD1 (polycystic kidney hepatic disease 1) involves a protein, fibrocystin, that is also localized to cilia/basal body and complexes with PKD2. This large, receptor-like protein is thought to be involved in the tubulogenesis and/or maintenance of duct-lumen architecture of epithelium.
• Rare syndromic forms of PKD include defects of the eye, central nervous system, digits, and/or neural tube.3
• A variant of PKD is glomerulocystic kidney (GCK), which refers to a kidney with greater than 5% cystic glomeruli.5 This condition is usually diagnosed in young patients. Although PKD-associated gene mutations have been excluded in many cases, there is a familial form of GCK presenting with cystic kidneys, hyperuricemia, and isosthenuria (concentration similar to plasma).5

Family history is a useful tool for diagnosing early ADPKD.

Clinical Features

• Chronic flank pain as a result of the mass effect of enlarged kidneys.
• Acute pain with infection, obstruction, or hemorrhage into a cyst.
• Enlarged liver.
• Hypertension is common in adults (75%) and may be present in 10% to 30% of children.
• Kidney stones (calcium oxalate and uric acid) develop in 15% to 20% of affected individuals because of urinary stasis from distortion of the collecting system, low urine pH, and low urinary citrate.
• Nocturia may also be present from impaired renal concentrating ability.

Laboratory Testing

• Gross or microscopic hematuria (60%).2 Obtain a urinalysis to document hematuria and a complete blood count or hemoglobin to identify anemia.

Imaging

• Diagnosis often made with ultrasound. More than 80% of patients have cysts present by age 20 years and 100% by age 30 years. In one study, the sensitivity of ultrasound in at-risk individuals younger than age 30 years was 70% to 95%, depending on the type of PKD present.6 For younger patients or those with small cysts, CT scan (Figures 70-1 and 70-2) or MRI may be preferred.
• Cysts are commonly found in the liver (50% to 80%) (Figure 70-2), spleen, pancreas, and ovaries.
• The diagnosis of PKD can usually be made from ultrasound characteristics, the presence or absence of extrarenal abnormalities, and screening of parents older than 40 years of age.7 Age-dependent ultrasound criteria have been established for both diagnosis and disease exclusion in subjects at risk of PKD1 (the more severe disorder).8
• If the diagnosis is uncertain, genetic testing is available for both ADPKD and ARPKD.

See Reference 2.

• Simple cyst—Diagnosed at any age; few cysts seen; benign features.
• Acquired cystic disease—Diagnosed in adulthood; few to many cysts; cyst development preceded by renal failure.
• Tuberous sclerosis—Diagnosed at any age; few to many renal angiomyolipomas; inherited nonmalignant tumors grow in the skin, brain/nervous system, kidneys, and heart.

The current role of therapy in PKD is to slow the rate of progression of renal disease and minimize symptoms. However, specific treatments are on the horizon.

Nonpharmacologic

• Neither protein restriction nor tight blood pressure control decreased the decline in glomerular filtration rate (GFR) in clinical trials.9,10 However, in a UK population study, increasing coverage (from 7% to 46% of the population prescribed an antihypertensive agent) showed a trend towards decreasing mortality and increased intensity of antihypertensive therapy was associated with decreasing mortality in people with ADPKD.11
• For episodes of gross hematuria, one author recommends bed rest, analgesics, and hydration sufficient to increase the urinary flow rate to 2 to 3 L/day; hematuria generally declines to microscopic levels in a few days.2 SOR C

Medications

• Control blood pressure to reduce the risk of associated cardiovascular disease. SOR A
• In one randomized controlled trial (RCT) (N = 46 patients with ADPKD and hypertension), no differences in renal function, urinary albumin excretion, or left ventricular mass index were detected between those treated with ramipril versus metoprolol, during 3 years of follow-up.12 Renal function declined significantly in both groups. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the traditionally used agents for patients with chronic kidney disease and hypertension. SOR A
• Treat infection as early as possible. If pyocyst is suspected, agents that penetrate cysts such as trimethoprim-sulfamethoxazole, chloramphenicol, and ciprofloxacin are used. SOR C
• Future therapies focus on exploiting signaling mechanisms underlying disease pathogenesis. Experimental and observational studies suggest that the mammalian target of rapamycin (mTOR) pathway plays a critical role in cyst growth.
• A 2-year RCT of the mTOR inhibitor everolimus for patients with ADPKD (N = 46) demonstrated a slowing of the increase in total kidney volume over placebo but not the progression of renal impairment.13 An open-label trial (N = 100 patients with ADPKD and early chronic kidney disease) of the mTOR inhibitor sirolimus did not show slowing of kidney growth or improved function over standard care.14
• In a RCT of octreotide (a long-acting somatostatin analog) versus placebo for patients with polycystic liver disease (some of whom had ADPKD), patients with ADPKD randomized to octreotide had a stabilization of kidney volume (versus an increase in the control group) and all patients randomized to treatment showed a reduced liver volume; there was no difference between groups in GFR.15

Surgery and Other Procedures

• Cyst puncture and a sclerosing agent (i.e., ethanol) can be used in painful cysts. SOR C
• For painful liver enlargement, partial hepatectomy can be performed, with good outcomes reported at experienced centers.2 SOR C
• For patients with ESRD as a result of PKD, transplantation and dialysis are options.
• In a nationwide study of 15-year outcomes following renal transplantation (N = 534 patients with ADPKD and 4779 patients without ADPKD), patients with ADPKD had better graft survival and no difference in infections, but more thromboembolic complications, more metabolic complications, and increased incidence of hypertension.16

Referral

• Patients with PKD with progressive renal failure and/or ESRD should be managed by a team of providers as they often require dialysis or kidney transplantation and can develop multiple complications; other considerations include anemia management, aneurysm screening pretransplantation, and nephrectomy of the native ADPKD kidneys.17 SOR C
• Consider hospitalization for patients with PKD who develop acute pyelonephritis and symptomatic cyst infection.2

• Approximately 50% of patients with ADPKD progress slowly to ESRD; kidney failure requiring renal-replacement therapy typically develops in the fourth to sixth decade of life.2 Patients with ADPKD and ESRD may have more favorable outcomes compared to those with other causes of kidney failure.16
• The following are the characteristics that predict a faster rate of decline in GFR in persons with ADPKD18:
  • Greater serum creatinine (independent of GFR).
  • Greater urinary protein excretion.
  • Higher mean arterial pressure (MAP).
  • Young age.
  • Increased kidney volume (>1500 mL).2
  • Disease caused by PKD1 mutation.19
  • The presence of tubulointerstitial fibrosis.20
• The ARPKD phenotype is highly variable ranging from causing neonatal death to causing minimal kidney disease presenting later in life.3
• Patients with ADPKD are also more prone to kidney stones (Chapter 68, Kidney Stones).21

• Monitor patients renal function and watch for hypertension and posttransplantation diabetes mellitus; imaging to assess the rate of increased kidney and total cyst volume may be useful in prognosis.22
• Avoid exogenous estrogen use for women with ADPKD and liver cystic enlargement; consider limiting use in women with liver cysts.2
• For all patients with PKD with renal dysfunction, review medications to adjust for level of kidney function and avoid nephrotoxic drugs if possible. SOR C
• The prognosis for patients following renal transplant is fairly good. In a follow-up study of patients with autosomal dominant PKD, adult cadaveric renal transplant survival at 5 years was found to be 79%.23
• In the absence of a family history of aneurysm, screening is not routinely recommended for asymptomatic patients; diagnostic testing should be considered in patients with ADPKD and new-onset or severe headache or other central nervous system symptoms or signs.2
• Posttransplantation, patients with ADPKD may be more prone to the development of diabetes mellitus (odds ratio 2.3, 95% confidence interval, 1.008 to 5.14).24

• Explain the genetics (among patients with ADPKD disease will develop in half of their offspring) and prognosis to patients. Referral to a genetic counselor may be useful for patients considering childbearing.
• Hypertension is common and should be treated.
• Kidney dysfunction is also common and should be monitored.
• Avoid high-impact sports in which abdominal trauma may occur (e.g., boxing).2
• In otherwise healthy women with ADPKD, pregnancy is usually uncomplicated but the risks of severe hypertension and preeclampsia are higher than those in the general population when elevated blood pressure or renal insufficiency is present before conception.25

Patient Resources

• National Kidney Foundation (800-622-9010)—http://www.kidney.org.
• National Kidney Disease Education Program—http://www.nkdep.nih.gov.
• National Institutes of Health, PubMed Health. PolycysticKidney Disease—http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001531/.

Provider Resources

• Roser T. Polycystic Kidney Disease—http://emedicine.medscape.com/article/244907.