Etiology

Two genes have been identified in autosomal-dominant PKD (ADPKD): PKD1 (chromosome region 16p13.3), which is found in around 85% of cases and encodes the protein polycystin 1; and PKD2 (4q21), found in around 15% of cases and encodes polycystin 2. The current theory is that a wild-type copy of the gene develops an inactivating somatic mutation in a minority of cells, leading to loss of polycystin function and clonal cyst development. [20] The protein products of PKD1 and PKD2, polycystin 1 [21] [22] and polycystin 2 [23] are membrane proteins that form a functional complex, but so far, no extracellular ligands for polycystin 1 have been identified. [24] [25] [26] [27] [28] Polycystin 2 is a nonselective cation channel capable of transporting calcium ions. [29] [30] [31] Recent evidence points to a role for the polycystins in the renal tubule primary cilium acting as a mechanosensitive cation channel. [32] Polycystin 1, polycystin 2, and the autosomal-recessive PKD (ARPKD) protein have been found in urine in membranous vesicles known as exosomes. [33]

Pathophysiology

Renal cysts develop and grow over time, leading to compression of the normal renal architecture and intrarenal vasculature, increased renal size, interstitial fibrosis and tubular atrophy, and progressive renal impairment. [34] com.bmj.content.model.Caption@21adf93a [Figure caption and citation for the preceding image starts]: Gross pathology of polycystic kidneys Adapted from Dr Edwin P. Ewing, Jr., Public Health Image Library, CDC (1972) [Citation ends]. Cysts develop from cells in the tubular portion of the nephron and collecting ducts. Although all cells are programmed with an autosomal-dominant PKD (ADPKD) mutation, only a minority develop cysts.

Based on findings of the landmark Modification of Diet in Renal Disease (MDRD) study, ADPKD patients had the most rapid decline of renal function of all forms of chronic kidney disease. [35] Most patients with PKD1 mutations have renal failure by the age of 70 years, whereas >50% of patients with PKD2 mutations have adequate renal function at the same age. Mean age of onset of ESRD is 54 years with a PKD1 mutation and 74 years with PKD2. [1] Patients with mutations in the 5' region of PKD1 have more severe disease (18.9% versus 39.7% with adequate renal function at 60 years of age) and are more likely to have intracranial aneurysms and aneurysm ruptures than are patients with 3' region mutations. [2] [3] No clear correlations have been found with mutation type in PKD1, or with mutation type or position in PKD2. [4]

Additional disease-specific complications and morbidity arise from hepatic involvement, valvular heart disease, intracranial aneurysms, pain, massive kidney enlargement, and diverticular disease, contributing to additional morbidity and mortality. [36]

In autosomal-recessive PKD, renal cysts arise from collecting ducts, and congenital hepatic fibrosis is characteristic. [37] [38]

Classification

Autosomal-dominant polycystic kidney disease (ADPKD)

ADPKD is genetically heterogeneous with 2 genes identified:

  • PKD1 (chromosome region 16p13.3), which is found in around 85% of cases and encodes the protein polycystin 1

  • PKD2 (4q21), which is found in around 15% of cases and encodes polycystin 2.

Most patients with PKD1 mutations have renal failure by the age of 70 years, whereas >50% of patients with PKD2 mutations have adequate renal function at the same age. Mean age of onset of ESRD is 54.3 years with a PKD1 mutation and 74 years with PKD2. [1]

Patients with mutations in the 5' region of PKD1 have more severe disease (18.9% versus 39.7% with adequate renal function at 60 years of age) and are more likely to have intracranial aneurysms and aneurysm ruptures than are patients with mutations in the 3' region. [2] [3] No clear correlations have been found with mutation type in PKD1, or with mutation type or position in PKD2. [4]

Autosomal-recessive polycystic kidney disease (ARPKD)

Patients with ARPKD often present in the neonatal period with enlarged echogenic kidneys; in these cases there is a high mortality rate in the first year of life, with many requiring ventilation. [5] For patients who survive the neonatal period, the probability of survival to 15 years of age ranges from 50% to 80%, and many of them will not require renal replacement therapy at that stage. This monograph does not deal with ARPKD.

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