The cyst formation in ADPKD is known to derive from mutations inPKD1andPKD2genes encoding the proteins polycystin-1 and polycystin-2, respectively. The PKD1 gene mutation involves approximately 85% cases of ADPKD and these individuals usually show more severe disease with early cyst development and are more likely to progress to ESRD. The possession of two identical forms of PKD1 gene, one inherited from each parent (i.e. PKD1 homozygosity) is known to be lethal in utero [91]. The PKD2 gene mutation is known to affect the remaining 15% cases. However, studies on some families with ADPKD have found neither PKD1 nor PKD2 mutations, postulating that an additional genetic loci may be associated with the disease [4, 15, 36, 85, 139]. The latter two categories of patients (PKD2 gene or postulated additional
1.3 Pathogenesis of ADPKD 5
genetic loci) are known to present with milder form of the disease but there is also evidence on families with severe clinical courses [4, 36]. In case of heterozygous mutations involving both PKD1 and PKD2 gene, the severity of disease is worse than mutation of a single gene [93]. The course of disease severity has also been linked to inheritence from each parent. It has been suggested that patients inheriting ADPKD from their father experience less severe disease compared to inheritence from the mother [10].
Previous studies have indicated the initiation of renal cyst development in renal tubules and in rare cases the Bowman’s capsule [46]. At first, the cysts appear as tiny growths in the renal tubule and eventually expand relentlessly. For several decades, however, the cell proliferation in ADPKD is relatively low but this allows individual cysts to remarkably increase in size (even>10 cm in diameter) and the combined effect of increased cell proliferation and fluid secretion promotes progressive cyst enlargement [45]. The rate of cyst growth is not significantly different between PKD1 and PKD2 mutations, however, the median age for onset of ESRD is approximately 53 years in patients with PKD1 mutation while, it is estimated to be around 69 years in patients with PKD2 mutation [50]. The prevalence of all cystic manifestations in ADPKD increases with age but no specific pattern of cyst growth has been identified so far and investigations have only suggested that increase in the cyst volume is largely individualized, varying from patient to patient. For every individual with ADPKD, each cyst in a polycystic kidney is considered to function independently, but known to have a constant growth rate. The overall growth of all these individual cysts in both kidneys causes an exponential increase in thetotal kidney volume(TKV), with the oldest and largest cysts accounting for greater effect on the TKV change compared to the younger and smaller cysts [45]. The gross pathology of polycystic kidneys is shown in figure 1.3, depicting independent and heterogeneous growth of cysts in individual kidneys. The variation in kidney shape, size, and volume of polycystic kidneys in comparison to normal kidneys, as well as
Fig. 1.3. Gross Pathology of Polycystic Kidneys. In ADPKD, increase in the cyst volume is largely individu-alized, varying from patient to patient. For every individual with ADPKD, each cyst in a polycystic kidney is considered to function independently but known to have a constant growth rate. Eventually, overall growth of all these individual cysts causes an exponential increase in the TKV. (Image courtesy:
phil.cdc.gov/PHIL_Images/02071999/00002/20G0027_lores.jpg)
6 Chapter 1 Introduction
Fig. 1.4. Three-dimensional representation of ADPKD kidneys in comparison with normal kidneys.Scales represent dimension in cm. The kidney shape, size, and volume highly differ between the normal control (panel A:T KV = 591ml) and the patients (panel B:T KV = 1,327ml; panel C:T KV = 3,026ml;
panel D:T KV = 5,836ml). TKV is the combined volume of left and right kidneys.
the variability among different ADPKD patients is depicted in figure 1.4. The volume and shape of ADPKD kidneys can vary considerably among different patients. Some polycystic kidneys adopt regular shape but most patients have markedly irregular shaped kidneys with prominent surface irregularities due to the presence of different sized and shaped cysts.
Manifestations of ADPKD also include development of hepatic cysts (70%) and pancreatic cysts (5%), which may spread to the spleen, prostate and seminal vesicles. The number and size of hepatic cysts has shown to correlate with female gender and, severity of the renal disease [16]. Other risks include increased chances of heart valve abnormalities and aneurysms in aorta [133] or in blood vessels at the base of the brain [24]. Moreover, associated clinical symptoms of ADPKD such as hypertension (blood pressure 140/190 mmHg), hematuria, and abdominal pains due to passage of stones and urinary tract infection [136] can lead to renal insufficiency. ADPKD patients progressing to ESRD require hemodialysis, peritoneal dialysis or renal transplantation.
To identify potential drug treatments for slowing down or even halting ADPKD progression, it is vital to recognise effective biomarkers and their response to new therapies. TKV has been identified as an important imaging biomarker for assessment of disease severity and for predicting disease progression in ADPKD. In the next section, we describe different imaging techniques for monitoring morphological changes in the kidneys to aid TKV computation in ADPKD.
1.3 Pathogenesis of ADPKD 7