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Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Review literature: (Kuehn and Walz, 2007)
Definition of Autosomal Dominant Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease is an inherited cystic renal disease with development of end-stage renal disease in adulthood.
- Incidence 1:2000
- 15% of dialysis patients are suffering from ADPKD
Etiology of Autosomal Dominant Polycystic Kidney Disease
Variations in two genes are known to cause aut. dom. polycystic kidney disease. In 85–90% of patients with ADPKD, mutations in PKD1 (chromosome 16, coding for polycystin-1) are responsible for the disease. In 10–15%, mutations of PKD2 (chromosome 4, coding for polycystin-2) are responsible. ADPKD caused by mutations of PKD2 has usually a later onset and slower progression of disease. Autosomal dominant inheritance with almost 100% penetrance is typical, so that 50% of children will inherited the disease from affected patients. The disease occurs in accordance with Knudson's theory of two hits: one diseased gene is inherited, the second copy of the gene is damaged by a spontaneous mutation and explains the long asymptomatic latency in the onset of the disease.
Polycystin-1 and polycystin-2 have important functions in signal transduction and in the formation of the primary cilium of the tubular epithelial cells. The disturbed function of polycystin leads to a proliferation of the tubular epithelium and to the formation of cysts; every part of the nephron may be affected. Similar mechanisms may damage blood vessels and other organ systems. The disease leads to activation of mTOR signaling, enhances cAMP production and increases ion and fluid secretion into the renal cystic lumen. The vasopressin V2-receptor blocker tolvaptan inhibits ADH dependent cAMP production, slows the increase in kidney volume and delays the development of renal insufficiency.
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 by 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).
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 a tubulus of the nephron. The epithelium of the cyst corresponds to the origin.
Cysts are also formed in other organ systems, see section signs and symptoms [fig. liver cysts].
Polycystic kidneys due to autosomal dominant polycystic kidney disease (ADPKD): both organs are greatly enlarged and show multiple cysts. Figure by Dr. Edwin P. Ewing, Jr. Public Health Image Library, Center for Disease Control and Prevention, USA, www.cdc.gov.
Liver cysts in autosomal dominant polycystic kidney disease (ADPKD). Figure from Dr. Edwin P. Ewing, Jr. Public Health Image Library, Center for Disease Control and Prevention, USA, www.cdc.gov.
Signs and Symptoms
Onset of disease:
Symptoms start with the age of 30 to 50 years. Renal ultrasound and genetic screening lowers the average age of initial diagnosis due to the discovery of the asymptomatic disease. Rarely, the disease begins in infancy.
- Hematuria (50%)
- Flank pain and fever (cyst rupture or cyst infection)
- Gastrointestinal symptoms due to large kidneys
- Arterial hypertension (80%)
- End-stage renal disease and symptoms of uremia in the fifth dekade (PDK1 mutation) or seventh dekade (PDK2 mutation)
Manifestations in further organs:
- Cysts in the liver, pancreas, spleen and lungs
- Aneurysm of the cerebral arteries
- Colonic diverticula
- Mitral valve prolapse
Diagnostic Work-Up of Autosomal Dominant Polycystic Kidney Disease
covering at least three generations.
- Urine analysis for proteinuria
- Creatinine or/and cystatin C to evaluate renal function.
- Genetic evaluation: for the differential diagnosis of unclear cystic kidney disease and as a predictive diagnosis in case of a positive family history. A parent with ADPKD has a 50% chance of having a child with the same condition (autosomal dominant inheritance pattern). Genetic predictive testing is very expensive and offer few if any clinical advantages compared to screening with imaging (see following section).
Renal imaging enables an eary diagnosis of patients at risk (with a positive family history). The diagnosis of ADPKD is certain in patients at risk, if there are at least two unilateral renal cysts or bilateral renal cysts at an age below 30 years, or at least two renal cysts in each kidney (30–60 years old). Further ultrasound imaging should focus on the liver, pancreas and spleen. If cysts are not detectable in the kidneys or visceral organs at the age of 40 years, a patient at risk is considered healthy (Ravine et al, 1994). The determination of the bilateral renal volume is important for affected patients to evaluate the prognosis of the renal function (see above). Later in the disease, the kidneys are massively enlarged and completely filled by cysts
- Abdominal CT: imaging of renal cysts, e.g. if flank pain has to be evaluated.
- Cranial CT: to estimate the risk of intracranial bleeding due to aneurysms.
- Bilateral renal enlargement
- Calyceal stretching by cysts [fig. intravenous urography in ADPKD]
- Swiss cheese aspect in nephrogram phase
The risk for children of affected parents is 50%. A genetic evaluation and/or sonography and advice to the children of the patients should be offered.
Treatment of Autosomal Dominant Polycystic Kidney Disease
Early therapy of arterial hypertension with ACE inhibitors or angiotensin-II receptor antagonists. Low-salt diet. Protein reduction does not improve the prognosis. The vasopressin (V2) receptor antagonist tolvaptan is approved in patients at high risk of progression (age <30 years, renal volume >1500 ml and GFR <90 ml) to slow down disease progression (Torres et al, 2012). It is realistic to postpone dialysis for 4–6.5 years. Polyuria (sometimes over 7 l/d) and idiosyncratic hepatotoxicity are problematic side effects, which require intensive patient monitoring.
Management of Flank Pain:
Nephrolithiasis, bleeding or infection of cysts may be responsible for flank pain. If imaging can reveal altered cysts, percutanous management (cyst aspiration and sclerotherapy) or laparoscopic unroofing of cysts may be helpful. Studies show contradictory results.
Treatment of Renal Failure:
Hemodialysis and renal transplantation are the treatment alternatives. Nephrectomy is often necessary before renal transplantation: either to create room for the transplant or if recurrent symptoms from the enlarged polycystic kidneys are present.
Experimental Treatment Approaches:
Limitation of tubulus epithelium proliferation by inhibitors of signal transduction. Previous studies with mTOR inhibitors, such as everolimus, have failed to demonstrate any protective effect on renal function. Future prospects include EGFR tyrosine kinase inhibitors or somatostatin analogues (Walz et al, 2010).
Prognosis of Autosomal Dominant Polycystic Kidney Disease (ADPKD):
Overall prognosis has become better due to improved treatment options of complications like urinary tract infection, nephrolithiasis, hypertension or renal insufficiency.
ADPKD leads to dialysis in 2% by the age of 40, 23% by the age of 50 and 48% by the age of 73. The risk for end-stage renal disease correlates closely with the kidney volume (see above).
9% of patients with ADPKD die of subarachnoid hemorrhage (ruptured brain aneurysm). In addition, cerebral hemorrhage due to malignant hypertension is possible.
Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
- W. Kuhn and G. Walz.
- Autosomal dominante polyzystische nierenerkrankung.
Dtsch Arztebl, 104 (44): 3022–8, 2007.
- Walz, G.; Budde, K.; Mannaa, M.; Nürnberger, J.; Wanner, C.; Sommerer, C.; Kunzendorf, U.; Banas, B.; Hörl, W. H.; Obermüller, N.; Arns, W.; Pavenstädt, H.; Gaedeke, J.; Büchert, M.; May, C.; Gschaidmeier, H.; Kramer, S. & Eckardt, K.
- Everolimus in
patients with autosomal dominant polycystic kidney disease.
N Engl J Med, 2010, 363, 830-840
Deutsche Version: ADPKD