Cystic Diseases Of The Kidneys

Cystic diseases of the kidneys  There are many types of cystic diseases in the kidney and the most common type is polycystic kidneys – particularly the Autosomal dominant polycystic kidney disease (ADPKD). At least two genes account for this disorder: ADPKD1 on the short arm of chromosome 16 (85–90% of patients) and ADPKD2 on chromosome 4 (10–15%). Patients with the PKD2 mutation have slower progression of disease and longer life expectancy than those with PKD1. However, other sporadic cases without these two gene mutations have also been recognised Renal manifestations of ADPCKD   The main manifestation is progressive renal failure due, in part, to continued enlargement of cysts. Others include: o Hypertension o UTI o Concentrating defect o Haematuria o Nephrolithiasis (50% uric acid, 50% calcium oxalate stones) o Acute or chronic flank and abdominal pain o Renal cell carcinoma Extrarenal manifestations include: o Cerebral aneurysms (20%) o Hepatic (30%), splenic (10%) and pancreatic (5%) cysts o Cardiac valve disease, mainly mitral and aortic valves o Left ventricular hypertrophy o Colonic diverticula o Abdominal wall and inguinal hernia Diagnosis    In symptomatic individuals, the following factors are used for diagnosis: o Family history of ADPCKD o Renal manifestations o Extrarenal manifestations o Ultrasound/CT findings There may be a negative family history. In 25% of cases, clinical presentation and imaging studies alone suggest a diagnosis of ADPCKD. In most cases, the disease is inherited, but the affected parent may have died without a diagnosis or is alive with a mild form of the undetected disease. In 5% of cases, the disease may be due to a new mutation. Diagnosis should be strongly suspected in the presence of multiple and bilateral cysts (defined as 10 or more cysts in each kidney), as well as in the absence of findings suggestive of a different renal cystic disease. Genetics of ADPKD and the mechanisms of cyst growth      ~ 85 % have a defect on chromosome 16 (PKD1 locus) ~ 15% have a defect on chromosome 4 (PKD2 locus) with a less severe phenotype than PKD1 PKD1 and PKD2 encode proteins called polycystin-1 (localised in primary cilia in renal tubular epithelia, responsible for cell-cell and cell-matrix interactions) and polycystin-2 (in distal tubules, collecting duct, and thick ascending limb, and is involved in cell calcium signalling) respectively. The leading hypothesis is that the abnormalities in the renal cilia due to polycystin mutations contribute to renal cyst formation PC-1 and PC-2 contribute to fluid-flow sensation by primary cilium in the renal epithelium, and they both function in the same mechanotransduction pathway. Loss of dysfunction of PC-1 or PC-2 can lead to PKD owing to the inability of the cells to sense mechanical cues that normally regulate tissue morphogenesis Cyst growth  The cilia bend by fluid flow and initiate a Ca 2+ influx that prevents cyst formation.  The tubular epithelial cells undergo oriented cell division during tubular elongation, along the axis of the anterior-posterior axis of the nephron.  The cilium or basal body/centrosome complex may provide spatial cues to position the centrosome and mitotic spindle before the next cell division.    A failure to communicate this spatial information (e.g. mutation) may condemn tubular epithelial cells to proliferate and to form cysts. Early cysts begins as dilatations in the intact tubules and fill by glomerular filtration. Enlarging cysts lose connection to functioning nephrons, due to fibrosis in the surrounding interstitium. Cyst growth results from the secretion of fluid into the cysts and is associated with hyperplasia of the cyst epithelium, reflecting maturational arrest. Treatment       Inhibition of fluid secretion o Vasopressin receptor antagonists lower renal epithelial cell intracellular cAMP levels Inhibition of cell proliferation o Rapamycin and lovastatin Cyst drainage Control of hypertension Alkali therapy Note: surgical options may also need to be considered, such as partial or complete renal resection