Progression of chronic kidney disease in familial LCAT deficiency: a follow-up of the Italian cohort

Abstract

Familial LCAT deficiency (FLD) is a rare genetic disorder of HDL metabolism, caused by loss-of-function mutations in the LCAT gene and characterized by a variety of symptoms including corneal opacities and kidney failure. Renal disease represents the leading cause of morbidity and mortality in FLD cases. However, the prognosis is not known and the rate of deterioration of kidney function is variable and unpredictable from patient-to-patient. In this paper, we present data from a follow-up of the large Italian cohort of FLD patients, who have been followed for an average of 12 years. We show that renal failure occurs at the median age of 46 years, with a median time to a second recurrence of 10 years. Additionally, we identify high plasma unesterified cholesterol level as a predicting factor for rapid deterioration of kidney function. In conclusion, this study highlights the severe consequences of FLD, underlines the need of correct early diagnosis and referral of patients to specialized centres, and highlights the urgency for effective treatments to prevent or slow renal disease in patients with LCAT deficiency.

High-Density Lipoproteins and the Kidney

“…Indices of renal function such as serum creatinine and creatinine clearance usually remain normal in the first three decades of life [ 88 ]. Due to the rarity of the disease, the natural history of FLD is still largely unknown; however, a recent work has analyzed the progression of the disease in 18 FLD carriers followed, in some cases, for more than two decades [ 89 ]. In this Italian cohort, half of the FLD patients had the first renal event, classified as kidney failure or kidney transplantation or death for renal complications, by the age of 46 years, with median time to a second event of 10 years [ 89 ].…”

“…Due to the rarity of the disease, the natural history of FLD is still largely unknown; however, a recent work has analyzed the progression of the disease in 18 FLD carriers followed, in some cases, for more than two decades [ 89 ]. In this Italian cohort, half of the FLD patients had the first renal event, classified as kidney failure or kidney transplantation or death for renal complications, by the age of 46 years, with median time to a second event of 10 years [ 89 ]. Even within the same family, the development and progression of renal damage in FLD patients are highly variable [ 52 , 77 ], suggesting that different genetic and environmental factors can impact on kidney deterioration.…”

“…Even within the same family, the development and progression of renal damage in FLD patients are highly variable [ 52 , 77 ], suggesting that different genetic and environmental factors can impact on kidney deterioration. Interestingly, in this cohort the plasma level of unesterified cholesterol at diagnosis predicted the rate of progression of renal events (dialysis, kidney transplantation, or death for renal complications), and patients with unesterified cholesterol values above the median showed lower event-free survival [ 89 ]. The excess of unesterified cholesterol in these patients accumulates in LpX, which deposits in the kidney [ 86 ].…”

“…No established therapy is currently available for FLD patients, and pharmacological approaches are aimed at correcting the dyslipidemia typically associated with the disease and at delaying the evolution of chronic nephropathy. Renal transplantation represents an option in FLD cases with kidney failure; however, because transplantation does not correct the underlying enzymatic defect, the disease can rapidly reoccur [ 89 ]. Enzyme replacement therapy represents an option, and recombinant LCAT is currently under clinical development [ 90 , 91 ].…”

Current Status of Familial LCAT Deficiency in Japan

“…The reaction requires the presence of helical apolipoproteins such as apolipoprotein (apo) A-I and E. It takes place on HDL, where particles are initially assembled as disclike particles from extracellular helical apolipoproteins of 3.56 mL/min/1.73 m 2 , whereas deterioration in heterozygous members and family controls was 1.33 and 0.68 mL/min/1.73 m 2 , respectively 36) . A recent Italian cohort study in which 18 FLD patients (12 males and 6 females) were followed up for 12 8.5 years reported that renal events (dialysis, kidney transplant, or death due to renal complications) occur at a median age of 46 years 37) .…”