Polycystic kidney disease
- Autosomal dominant polycystic kidney disease (ADPKD) can progress to renal failure in mid-adulthood. Caused by mutations in:
- Autosomal recessive polycystic kidney disease associated with the PKHD1gene at 6p21.1-p12 that codes for fibrocystin.
- Associations with a number of other genetic syndromes which are called ciliopathies
Autosomal Dominant Polycystic Kidney Disease
The precise mechanism underlying the disease is not fully understood. Present thinking is that patients have a defect of either the PKD1 or PKD2 gene and the cysts only form when rare further spontaneous mutations occur during organ development as knock out of both genes is needed for this phenotype to occur. Polycystin 1 appears to code a transmembrane protein with a significant extra-cellular component and several transmembrane domains. Its putative role appears to be cell-to-cell adhesion or signalling as well as cell-to-extra cellular matrix signalling. Polycystin 2 appears to be a membrane Ca2+-channel. Both localise to the cilium of renal tubular epithelial cells. These non-motile cilia project into the lumen of the tubules and may function as a mechanoreceptor that allows the epithelial cells to adapt to changes in luminal flow or mechanical stresses. It is thought that polycystin 1 and polycystin 2 may form a complex which may explain the similar phenotype. Dysfunction of the proposed complex results in altered cell proliferation, deranged cell signally and abnormal epithelial secretion, resulting in cyst formation.
85-90% of cases are caused by PKD1 mutations, while most of the remainder are PKD2 mutations. The range of genetic mutations is heterogenous. About 25% of cases are thought to arise by de novo mutations. Patients with PKD1 mutations tend develop end-stage renal failure several years earlier than those with PKD2 mutations.
The disease is insidious (with hypertension) and progressive. It may be asymptomatic until it causes haematuria, a dragging sensation, flank pain from haemorrhage into the cyst or infections. Cyst formation starts early in life, with end-stage renal failure being uncommon at age 40 (about 5%), but by age 70, >90% will have developed end-stage renal failure. It is a cause of hypertension, presumed to be due to compression of the renal arteries producing an effect equivalent to renal artery stenosis.
Apart from the renal manifestations, other clinical features include cystic changes in the liver, pancreas and lungs. There is also an association with mitral valve prolapse, berry aneurysms and diverticulosis.
Tolvaptan slows the progression of cyst development and renal insufficiency in ADPKD in adults with CKD stage 1 to 3 at initiation of treatment with evidence of rapidly progressing disease.
Autosomal Recessive Polycystic Kidney Disease
As the name suggests, the disease is autosomal recessive in inheritance. It presents earlier in life and may be a cause for still births or early neonatal death. Most patients will have end stage renal failure but their 20s. There is a close association with congenital hepatic fibrosis due to intrahepatic bile-duct dysplasia. Cysts in ARPKD tend to be radially arranged. Histologically, the cystic changes affect the collecting ducts of the cortex and medulla, sparing the remainder of the nephron unit. The gene PKHD1 codes for fibrocystin (polyductin) which is a membrane associated receptor-like protein that colocalises with polycystin-2 in the renal epithelial primary cilia.
- ↑ Hildebrandt F, Benzing T, Katsanis N. Ciliopathies. The New England journal of medicine. 2011 Apr 21; 364(16):1533-43.(Link to article – subscription may be required.)