Autosomal Dominant Polycystic Kidney Disease

Epidemiology

Prevalence: 300,000 to 600,000 patients in United States
Symptom onset most often after age 30 years
Responsible for 4.7% of End Stage Renal Disease in the United States

Pathophysiology

Formation of cysts in multiple organ systems, most notably in the Kidneys
1. PKD1 and PKD2 gene mutations result in signal dysregulation
  1. Increased cyclic Adenosine monophosphate and increased cytogenesis
2. Cysts form, expand and gradually result in nephron loss
3. Initial compensation via hyperfiltration by remaining renal tubules
  1. Ultimately is overcome and Renal Failure progresses
4. Once GFR starts to decline, it does so at a rate of 4.4 to 5.9 ml/minute/year
Inheritance in Autosomal Dominant pattern
1. A child has a 50% chance of inheriting ADPKD from an affected parent
Spontaneous mutation is responsible for 5% of cases

Types

PKD1 Gene: (86% of cases, 95% of cases in Caucasians)
1. ADPKD1 gene on short arm of Chromosome 16
2. PKD1 encodes integral membrane Protein Polycystin-1
3. End-stage renal disease average age of onset: 57
4. Associated with a higher risk of progression to end-stage renal disease than for the PKD2 gene mutation
PKD2 Gene: (14% of cases)
1. ADPKD2 gene on Chromosome 4
2. PKD2 encodes integral membrane Protein Polycystin-2
3. End-stage renal disease average age of onset: 69

Symptoms

Symptom onset is delayed until patients are in their 30-40s
Flank or Abdominal Pain (60%) causes
1. Renal Cyst rupture
2. Enlarged Kidney compression of regional structures
3. Nephrolithiasis
4. Urinary Tract Infection
Gross Hematuria
Urinary Tract Infection symptoms

Signs

Hypertension
With advanced renal or hepatic disease, cyst-related mass effect may be palpable

Labs

Renal Function test monitoring
Urinalysis
Genetic screening indications
1. Not routinely indicated
2. Young, at risk asymptomatic patients with normal Ultrasound screening
3. Large Kidneys with Renal Cysts and no known Family History of ADPKD
4. Kidney Transplant potential donor who is at risk of ADPKD

Imaging

First-Line
1. Renal Ultrasound (effective, lower cost, no radiation)
Alternative screening (if non-diagnostic Ultrasound or large body habitus)
1. Abdominal CT
2. Abdominal MRI

Diagnosis

Ultrasound criteria for those at risk of ADPKD Type 1
1. Age <30 years: 2 or more cysts in one or both Kidneys
2. Age 30 to 59 years: 2 or more cysts in each Kidneys
3. Age >60 years: 4 or more cysts in each Kidneys
Ultrasound criteria for those at risk of ADPKD with unknown Genotype
1. Age 15 to 39 years: 2 or more cysts in one or both Kidneys
2. Age 40 to 59 years: 2 or more cysts in each Kidneys
3. Age >60 years: 4 or more cysts in each Kidneys
MRI criteria for those at risk of ADPKD
1. Age <30 years: 5 or more cysts in each Kidneys
2. Age 30 to 44 years: 6 or more cysts in each Kidneys
3. Age 45 to 59 years (males): 6 or more cysts in each Kidneys
4. Age 45 to 59 years (females): 9 or more cysts in each Kidneys
References
1. Pei (2009) J Am Soc Nephrol 20(1): 205-12 [PubMed]

Complications

Renal Failure (at least 45% of cases)
1. Accounts for 5-10% of End Stage Renal Disease (ESRD)
2. By age 70 years old, 80% have end-stage renal disease or have died of other cause
  1. Gabow (1993) N Engl J Med 329(5): 332-42 [PubMed]
Hypertension
1. Children: 30%
2. Adults: 60%
3. End Stage Renal Disease: 80%
Extra-Renal Cysts
1. Extra-Renal Cysts most commonly occur in the liver (34-78%)
2. Cysts also occur in the ovaries, Seminal Vessicles, Pancreas, Spleen and Central Nervous System
Left Ventricular Hypertrophy
Mitral Valve Prolapse (26%)
Aortic Insufficiency (due to aortic root dilitation)
Gross Hematuria (associated with Renal Cyst rupture)
Recurrent Urinary Tract Infection
Nephrolithiasis (20%)
Renal Cell Carcinoma
Cerebral Aneurysm (5-10%)
1. At least twice as likely as in the general population
2. Higher risk if Family History of Cerebral Aneurysm in addition to ADPKD
Colonic Diverticulum with risk of perforation
Inguinal Hernia

Risk Factors
End Stage Renal Disease

ADPKD1 gene
Early onset at young age
Male
Black race
Sickle Cell Trait
Hypertension
Left Ventricular Hypertrophy
Gross Hematuria
Proteinuria
Large renal volume
Hepatic Cysts
Urinary Tract Infections in males
Three or more pregnancies

Management

No specific interventions prevent cyst development
1. All management strategies are to evaluate and treat secondary complications and forestall end-stage renal disease
Hypertension control (Goal Blood Pressure < 140/90)
1. ACE Inhibitor
  1. Angiotensin Receptor Blocker may be used as an alternative if unable to use an ACE Inhibitor
2. Diuretic
  1. Caution when used with ACE Inhibitor
3. Calcium Channel Blocker
Urine changes
1. Proteinuria (30%)
2. Gross Hematuria
  1. Exclude Nephrolithiasis, Urinary Tract Infection, Abdominal Trauma, cyst rupture
  2. Exclude cancer (Renal Cell Carcinoma, Bladder Cancer) if Gross Hematuria persists >1 week or first time episode in age >50 years old
  3. Gross Hematuria is an independent risk factor for rapid progression of renal dysfunction (especially prior to age 30 years old)
  4. CT Abdomen and Pelvis will identify Nephrolithiasis, hemorrhagic Renal Cyst, Renal Mass and Traumatic Injury
  5. Most resolve spontaneously (including hemorrhagic Renal Cysts which resolves after 1 week)
  6. Maximize hydration
  7. Correct Coagulopathy if present
Flank and Abdominal Pain (e.g. cyst expansion related)
1. Exclude Nephrolithiasis if acute change
2. Analgesics (avoid NSAIDs due to nephrotoxicity)
3. Avoid provocative activities (e.g. Contact Sports, heavy lifting)
4. Consider pain management Consultation
5. Invasive measures
  1. Percutaneous cyst drainage and Alcohol sclerosis
  2. Open cyst reduction surgery
Urinary Tract Infection (and Renal Cyst infections)
1. Urinalysis and Urine Culture are typically positive
  1. However occult Renal Cyst infections may occur in the absence of Urine Culture growth
2. Organisms infecting Renal Cysts
  1. Escherichia coli (74% of cases)
  2. Staphylococcus aureus, Enterococcus, lactobacillus and Anaerobes account for remainder of Renal Cyst infections
3. Antibiotics with best renal parenchyma penetration
  1. Fluoroquinolones (best Renal Cyst penetration)
  2. Third Generation Cephalosporins (poor Renal Cyst penetration)
  3. Trimethoprim-sulfamethoxazole
Nephrolithiasis
1. ADPKD is associated with a two fold increased risk of Nephrolithiasis (and a 20% lifetime Prevalence)
2. Evaluate pain suggestive of Nephrolithiasis (e.g. Flank Pain) regardless of presence of Hematuria
Adult polycystic liver disease (Liver Cysts)
1. Liver function is typically preserved (with only a mild increase in Alkaline Phosphatase)
2. As with Renal Cysts, Hepatic Cysts may become infected or bleed
3. Avoid Estrogen (combination Oral Contraceptives or Estrogen Replacement Therapy) due to the risk of Hepatic Cyst proliferation
4. Symptoms if they occur are related to Hepatomegaly (but most often asymptomatic)
  1. Increased symptoms in pregnancy (due to hyperestrogenic state)
  2. Shortness of Breath or Lower Extremity Edema
  3. Early satiety or Esophageal Reflux
  4. Right Upper Quadrant Abdominal Pain or Low Back Pain
Intracranial Aneurysm
1. Occur in up to 5-10% of ADPKD patients (see above)
2. Screening indications (with non-contrast MRA using time-of-flight or inflow angiography)
  1. Before major elective surgery
  2. CNS symptoms (e.g. new or different Headache, Vomiting, lethargy, focal neurologic findings, Transient Ischemic Attack symptoms)
  3. Family History of Intracranial Aneurysm or Subarachnoid Hemorrhage
  4. High risk occupation (e.g. airplane pilot)
Pregnancy
1. Higher risk of maternal and fetal complications when ADPKD is accompanied by Hypertension
Renal Failure
1. See Chronic Renal Failure

References