Chapter 215

## Abstract

Abstract

1. Autosomal dominant polycystic kidney disease (ADPKD) (MIM 173900) is the most common inherited renal disease, accounting for 4.8 percent of the end-stage renal disease (ESRD) population in the United States and is a systemic disorder involving the heart, liver, cerebral vasculature, and connective tissue. Clinical manifestations of this disorder are highly variable within and between families. The average age of presentation is in the fourth decade of life with invariable penetrance by the age of 70 years.

2. Diagnosis of ADPKD relies on multiple sources of information including medical history, physical examination, laboratory evaluation, renal imaging, and genetic analysis. Gene linkage analysis provides no information concerning the clinical severity of the disorder and is used primarily for screening potentially eligible renal donors. Ultrasound in the imaging procedure of choice used to make a phenotypic diagnosis of ADPKD due to its sensitivity as well as cost and lack of invasiveness. Individuals from autosomal dominant polycystic kidney disease type 1 gene and gene symbol (PKD1) families with a negative ultrasound after 30 years of age have a less than 5 percent chance of being carriers of the disease.

3. Polycystic liver disease is a common manifestation in ADPKD and is useful in differentiating ADPKD from other renal cystic disorders of the kidney. Polycystic liver disease presents approximately 10 years after renal cystic disease with women more severely affected than men. Birth control pill use, pregnancy, and postmenopausal estrogen use are associated with more progressive polycystic liver disease. Although liver cystic involvement can be massive, liver function continues to remain normal.

4. Intracranial aneurysms (ICA) occur in 8 percent of ADPKD individuals as opposed to 2 percent of the general population. ICA cluster in families with a family history of ICA and are often multiple. Smoking and hypertension are not risk factors for ICA development in ADPKD. Individuals with a positive family history of ICA should be screened using time-of-flight three-dimensional magnetic resonance angiography. Reoccurrence of ICA is common in ADPKD individuals with a previous ICA, usually at least 3 years after the initial observation, and occurs more often in those individuals where rupture has occurred.

5. Hypertension is the most common renal complication in ADPKD occurring in 60 percent of individuals with normal renal function and is associated with a faster rate of progression to renal failure. Activation of the renin-angiotensin-aldosterone system plays an important role in the pathogenesis of hypertension in this disorder. Preliminary results from long-term studies suggest that angiotensin converting enzyme inhibition, in contrast to conventional diuretic therapy, may be beneficial in preventing progression to renal failure in this disorder.

6. Multiple therapies have been prescribed in experimental animal models of ADPKD and have shown success in slowing functional and structural progression of the disease. These therapies have not yet been successfully applied to man. Specifically, protein restriction has not demonstrated a significant impact on slowing progression to renal failure in human ADPKD. However, study design may not have been adequate to demonstrate a true benefit of this intervention.

7. Genetic linkage studies suggest there are at least three forms of ADPKD. The most common form (≈85 percent), autosomal dominant polycystic kidney disease type 1 (ADPKD1) (MIM 601313), results from mutation of the PKD1 gene on chromosome 16p13.3. The autosomal dominant polycystic kidney disease type 1 gene and gene symbol (PKD2) gene, on chromosome 4q22, is mutated in most of the others. A very small fraction of families have disease unlinked to markers for either locus. The three forms have nearly identical clinical phenotypes, although autosomal dominant polycystic kidney disease type 2 (ADPKD2) (MIM 173910) is somewhat milder.

8. The PKD1 gene encodes a 14-kb mRNA that is translated into a 4302-amino-acid membrane glycoprotein called polycystin-1. It is predicted to have an N-terminal extracellular domain of ≈3000 residues, an odd number of transmembrane-spanning elements,106111 and a short cytoplasmic tail that interacts with a number of other proteins, including the PKD2 gene product, polycystin-2. Polycystin is postulated to function as a nonkinase-type receptor for cell-cell and/or cell-matrix interactions.

9. PKD2 encodes a 5.4-kb mRNA that is translated into a 968-amino-acid integral membrane protein predicted to have six transmembrane-spanning elements with intracellular N- and C-termini. Although polycystin-2 has modest homology to polycystin-1, it most closely resembles the family of voltage-activated calcium (and sodium) channels. Expression of a homologous gene, PKD2-like gene and gene symbol (PKDL) , suggests that polycystin-2 is likely to function as a cation channel protein.

10. The nearly identical clinical profiles that result from mutations of PKD1 and PKD2 suggest that their translation products are tightly linked in a common signaling pathway. A series of in vitro and in vivo studies show that the two proteins do, in fact, associate.

11. Genetic studies of cystic tissue from human ADPKD1 and ADPKD2 organs have identified clonal somatic mutations of the wild-type allele in individual cysts, suggesting a “two-hit” model of disease pathogenesis. The results of gene targeting studies of Pkd1 and Pkd2 in mice support this model.

12. In the murine Pkd1 and Pkd2 models, cyst formation begins at day E15. These studies suggest that loss of functional polycystin-1 or -2 below a critical threshold results in a block in the normal differentiation program of the kidney.

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