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Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Definition of Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic multisystem disorder characterized by progressive development of multiple renal cysts, progressive decline in kidney function during adulthood, hepatic cysts, and intracranial aneurysms.

Epidemiology

• Incidence 1:2000
• 7–15% of dialysis patients have ADPKD

Etiology of Autosomal Dominant Polycystic Kidney Disease

Genetics:

Most patients have pathogenic variants in two genes: in 85–90%, PKD1 (chromosome 16, encoding polycystin-1) is affected, and in 10–15%, PKD2 (chromosome 4, encoding polycystin-2) is affected. PKD2 mutations typically cause a milder disease course, with later onset and slower progression. More rarely, other genetic alterations cause ADPKD or an ADPKD-like phenotype. Autosomal dominant inheritance with very high penetrance is typical, so that 50% of the children of affected patients inherit the disease. The disease develops according to Knudson’s two-hit theory: one affected allele is inherited, and the second allele is altered later by a spontaneous mutation, which explains the long symptom-free latency before disease onset.

Pathophysiology:

Polycystin-1 and polycystin-2 have important functions in signal transduction and in the formation of the primary cilium of tubular epithelial cells. Dysfunction causes impaired cell polarity, proliferation of the tubular epithelium, and cyst formation; every segment of the nephron may be affected. Similar mechanisms damage blood vessels and other organ systems. The disease leads to activation of mTOR signaling, increased cAMP production, and increased ion and fluid secretion into the renal cyst lumen. The vasopressin V2 receptor blocker tolvaptan inhibits ADH-dependent cAMP production, slows the increase in kidney volume, and delays the development of kidney failure.

Progression factors:

The normal (bilateral) kidney volume is usually below 400 ml. In ADPKD, increasing renal volume is associated with decreasing renal function. The kidney volume can be measured either by MRI or renal ultrasound imaging: the greater the kidney volume, the worse the prognosis for renal function. The time to end-stage renal disease for a 30-year-old man depends on the renal volume: 10 years (renal volume 2000 ml), 18 years (1500 ml) or 21 years (1000 ml) (Kuehn et al., 2015).

Pathology:

Autosomal dominant polycystic kidney disease leads to enlarged kidneys with multiple cysts [fig. polycystic kidneys]. The cysts are a few millimeters to a centimeter in size and derive from tubules of the nephron. The epithelium of the cyst corresponds to its origin. Cysts also develop in other organ systems; see section signs and symptoms [fig. liver cysts].

Signs and Symptoms

Onset of Disease:

ADPKD usually becomes clinically apparent between 30 and 50 years of age. Increased screening with ultrasonography and genetic testing lowers the age at initial diagnosis.

Symptoms:

Typical symptoms and complications are arterial hypertension, hematuria, proteinuria, flank or abdominal pain, fever caused by infected renal cysts, and nephrolithiasis.

Associated Manifestations:

Cysts occur in the liver, pancreas, and other organs. Cerebral arterial aneurysms carry a risk of subarachnoid hemorrhage. There is an increased risk of colonic diverticula, valvular heart disease, and thoracic aortic ectasia.

Diagnostic Workup of Autosomal Dominant Polycystic Kidney Disease

Family History:

Obtain a family history over three generations, including kidney failure, cystic disease, and subarachnoid hemorrhage.

Laboratory Tests:

Perform urinalysis for proteinuria or hematuria and measure serum creatinine; measure C-reactive protein in symptomatic patients.

Genetic Testing:

Genetic testing is useful for the differential diagnosis of unclear cystic kidney disease and for predictive testing in patients with a positive family history and inconclusive imaging.

Ultrasonography:

In patients from affected families, renal ultrasonography establishes an early diagnosis if at least 2 unilateral or bilateral renal cysts are present before 30 years of age, or if at least 2 cysts are present in each kidney between 30 and 60 years of age. The liver, pancreas, and spleen should also be examined for organ cysts. If no cysts are detected in the kidneys or visceral organs by 40 years of age in patients from affected families, the individual is considered unaffected. Determination of bilateral kidney volume is important for prognostic assessment of later kidney failure. In later stages, the kidneys are massively enlarged and extensively replaced by cysts.

CT or MRI:

Cross-sectional abdominal imaging is indicated when ultrasonography is inconclusive, for precise determination of kidney volume, and in the setting of complications such as hemorrhage, infection, or nephrolithiasis. Cranial imaging may be used to assess the risk of intracranial aneurysms.

Intravenous Urography:

Intravenous urography has virtually no role in the routine diagnostic workup of ADPKD. The nephrographic phase shows a Swiss-cheese appearance and calyceal displacement by cysts.

Treatment of Autosomal Dominant Polycystic Kidney Disease

Conservative Treatment:

Treat arterial hypertension early with ACE inhibitors or angiotensin II receptor blockers. Recommend a low-salt diet. Protein restriction does not improve prognosis.

Tolvaptan:

The vasopressin V2 receptor antagonist tolvaptan is approved for patients at high risk of progression to slow the decline in kidney function. Tolvaptan delays the onset of dialysis by approximately 1 year for every 5 years of treatment. Polyuria, sometimes exceeding 7 L/day, and idiosyncratic hepatotoxicity require intensive patient monitoring.

Flank Pain:

Nephrolithiasis, hemorrhage, or cyst infection may cause flank pain. Cyst infection requires lipophilic antibiotics for several weeks. If imaging identifies abnormal cysts, percutaneous treatment with pigtail catheter drainage and sclerotherapy or laparoscopic cyst deroofing may be helpful.

End-Stage Kidney Disease:

Hemodialysis, peritoneal dialysis, and kidney transplantation are treatment options. Nephrectomy before transplantation is not routinely required; consider it only for recurrent severe infection, symptomatic nephrolithiasis, recurrent or severe cyst hemorrhage, refractory pain, suspected malignancy, or inadequate space for the graft.

Experimental Treatment:

Pharmacologic inhibition of tubular epithelial proliferation by signal-transduction inhibitors is under investigation. Studies of mTOR inhibitors such as everolimus and tyrosine kinase inhibitors have not demonstrated a protective effect on kidney function.

Prognosis of Autosomal Dominant Polycystic Kidney Disease

The prognosis of ADPKD has improved over recent decades because of better treatment options.

Kidney Failure:

The median age at end-stage kidney disease depends on the causative mutation and is 54–58 years for PKD1 mutations and 74–80 years for PKD2 mutations.

Cerebral Hemorrhage:

9% of patients die from subarachnoid hemorrhage caused by aneurysm rupture. Cerebral hemorrhage due to malignant hypertension is also possible.

References

Devuyst O, Torres VE, u. a. KDIGO 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Kidney International. 2025.

  Deutsche Version: ADPKD

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