Familial Amyloidotic Polyneuropathy: how transthyretin associated amyloidosis involves the kidney

Amyloidoses are diseases in which soluble proteins aggregate and form insoluble proteins that accumulate in extra-cellular spaces. The tissue deposits disrupt organ architecture and function and accompany or cause a wide range of systemic diseases. Transthyretin (TTR) is a beta-sheet-rich homotetrameric protein that must undergo rate-limiting tetramer dissociation and partial monomer unfolding to misassemble into amyloid and other aggregates. In familial amyloidotic polyneuropathy (FAP) of Portuguesetype, an amino acid substitution of methionine (M) for valine (V) at position 30 of TTR molecule (ATTR V30M) is present. FAP nephropathy has special epidemiological features with characteristic risk factors. The most important are age of onset of neuropathy, gender (female has higher risk) and presence of family history of renal disease. Low-penetrance of FAP has been found in the families of probands with endstage renal disease (ESRD). In TTR V30M gene carriers a stage of microalbuminuria can precede the onset of symptomatic neuropathy. The progression to overt renal disease develops in one half of patients with MA, usually 2 years after MA detection. Overall, one third of patients develop clinical nephropathy and 10% progress to ESRD. All patients have amyloid deposits in the kidney, even without renal expression of nephropathy. A more extensive glomerular and vascular involvement is present in patients with nephropathy. A peripheral sensitive neuropathy is the commonest first manifestation in nephropatic patients, unlikely, cardiac conduction disturbances have been observed as initial picture. Anaemia is present in one fourth of patients, even without renal failure, and erythropoietin levels are significantly lower than expected for the degree of anaemia. In our centre haemodialysis has been the option to treat ESRD (109 patients) but six patients underwent simultaneous kidney-liver transplantation. We do not register rejection episodes or clinical evidence of recurrence of kidney amyloidosis after the transplant. Finally, in this review we define a nephropatic type of FAP. Structural changes in TTR V30M variant, genetic or environmental factors may influence this particular phenotype.