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 article, 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 centers, and highlights the urgency for effective treatments to prevent or slow renal disease in patients with LCAT deficiency. 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 article, 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 centers, and highlights the urgency for effective treatments to prevent or slow renal disease in patients with LCAT deficiency. Familial LCAT deficiency (FLD) is a very rare autosomal recessive disorder of lipid metabolism caused by loss-of-function mutations in the LCAT gene (1Calabresi L. Simonelli S. Gomaraschi M. Franceschini G. Genetic lecithin:cholesterol acyltransferase deficiency and cardiovascular disease.Atherosclerosis. 2012; 222: 299-306Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). FLD patients have severe hypoalphalipoproteinemia and impairment of cholesterol esterification in plasma (2Calabresi L. Pisciotta L. Costantin A. Frigerio I. Eberini I. Alessandrini P. Arca M. Bon G.B. Boscutti G. Busnach G. et al.The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1972-1978Crossref PubMed Scopus (128) Google Scholar). Besides lipid abnormalities, homozygous and compound heterozygous FLD patients present corneal opacification, hemolytic anemia, and renal disease, which represents the primary cause of morbidity and mortality (3Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer H.B.J. Lecithin cholesterol acyltransferase deficiency and fish eye disease.in: Scriver C.R. Beaudet A.L. Sly W.S. The Metabolic and Molecular Bases of Inherited Diseases. McGraw-Hill, New York2001: 2817-2833Google Scholar). Proteinuria can develop as early as in the second decade of life (4Holleboom A.G. Kuivenhoven J.A. van Olden C.C. Peter J. Schimmel A.W. Levels J.H. Valentijn R.M. Vos P. Defesche J.C. Kastelein J.J. et al.Proteinuria in early childhood due to familial LCAT deficiency caused by loss of a disulfide bond in lecithin:cholesterol acyl transferase.Atherosclerosis. 2011; 216: 161-165Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar), and it unpredictably progresses to renal insufficiency and eventually to kidney failure (5Sessa A. Battini G. Meroni M. Daidone G. Carnera I. Brambilla P.L. Viganò G. Giordano F. Pallotti F. Torri Tarelli L. et al.Hypocomplementemic type II membranoproliferative glomerulonephritis in a male patient with familial lecithin-cholesterol acyltransferase deficiency due to two different allelic mutations.Nephron. 2001; 88: 268-272Crossref PubMed Scopus (12) Google Scholar, 6Imbasciati E. Paties C. Scarpioni L. Mihatsch M.J. Renal lesions in familial lecithin-cholesterol acyltransferase deficiency. Ultrastructural heterogeneity of glomerular changes.Am. J. Nephrol. 1986; 6: 66-70Crossref PubMed Scopus (30) Google Scholar). FLD patients are candidates for renal transplantation, but the disease can rapidly reoccur in the transplanted kidney within only a few years, as shown in a single reported anecdotal case (7Strøm E.H. Sund S. Reier-Nilsen M. Dorje C. Leren T.P. Lecithin:cholesterol acyltransferase (LCAT) deficiency: renal lesions with early graft recurrence.Ultrastruct. Pathol. 2011; 35: 139-145Crossref PubMed Scopus (21) Google Scholar). Although chronic kidney disease (CKD) etiopathogenesis is not completely understood, lipoprotein X (LpX), an abnormal lipoprotein enriched in unesterified cholesterol and relatively poor in other lipids and apolipoproteins, is involved in causing renal damage (8Ossoli A. Neufeld E.B. Thacker S.G. Vaisman B. Pryor M. Freeman L.A. Brantner C.A. Baranova I. Francone N.O. Demosky Jr., S.J. et al.Lipoprotein X causes renal disease in LCAT deficiency.PLoS One. 2016; 11e0150083 Crossref PubMed Scopus (33) Google Scholar). Currently, no effective treatment is available for FLD. Intervention is limited to the correction of lipid profile, through lipid-lowering drugs, and to the prevention and delay of renal failure, through renoprotective agents (9Aranda P. Valdivielso P. Pisciotta L. Garcia I. Garcã A-Arias C. Bertolini S. Martã N-Reyes G. Lez-Santos G. Calandra S. Therapeutic management of a new case of LCAT deficiency with a multifactorial long-term approach based on high doses of angiotensin II receptor blockers (ARBs).Clin. Nephrol. 2008; 69: 213-218Crossref PubMed Scopus (27) Google Scholar). However, there are no data about the real efficacy of these interventions. Hence, the prognosis of renal disease is not known and the rate of deterioration of kidney function is variable and unpredictable. Here, we report the follow-up of the Italian cohort of FLD patients (1Calabresi L. Simonelli S. Gomaraschi M. Franceschini G. Genetic lecithin:cholesterol acyltransferase deficiency and cardiovascular disease.Atherosclerosis. 2012; 222: 299-306Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 2Calabresi L. Pisciotta L. Costantin A. Frigerio I. Eberini I. Alessandrini P. Arca M. Bon G.B. Boscutti G. Busnach G. et al.The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1972-1978Crossref PubMed Scopus (128) Google Scholar, 10Bigazzi F. Dal Pino B. Pavanello C. Sbrana F. Aquaro G.D. Napoli V. Palmieri C. Barison A. Calabresi L. Sampietro T. Familial LCAT deficiency and cardiovascular disease: the game is not over. A case of dramatic multivessel atherosclerosis.Minerva Med. May 29, 2020; (Epub ahead of print.)doi:10.23736/S0026-4806.20.06633-1PubMed Google Scholar), one of the largest cohorts described, followed for up to 24 years. We collected clinical data from 18 Caucasian subjects (12 males and 6 females) with molecular confirmation of FLD, all belonging to the Italian cohort (1Calabresi L. Simonelli S. Gomaraschi M. Franceschini G. Genetic lecithin:cholesterol acyltransferase deficiency and cardiovascular disease.Atherosclerosis. 2012; 222: 299-306Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 2Calabresi L. Pisciotta L. Costantin A. Frigerio I. Eberini I. Alessandrini P. Arca M. Bon G.B. Boscutti G. Busnach G. et al.The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1972-1978Crossref PubMed Scopus (128) Google Scholar, 10Bigazzi F. Dal Pino B. Pavanello C. Sbrana F. Aquaro G.D. Napoli V. Palmieri C. Barison A. Calabresi L. Sampietro T. Familial LCAT deficiency and cardiovascular disease: the game is not over. A case of dramatic multivessel atherosclerosis.Minerva Med. May 29, 2020; (Epub ahead of print.)doi:10.23736/S0026-4806.20.06633-1PubMed Google Scholar). The group was comprised of 13 homozygous and 5 compound heterozygous for mutations in the LCAT gene. All procedures were followed in accordance with the ethical standards of the local institutional committees on human experimentation and according to tenets of the Helsinki Declaration of 1964, as revised in 2013. The study was approved by the internal ethics committee (approval number 446-092014). All patients provided written informed consent. In the case of deceased patients, consent was waived according to the Italian Data Protection Authority (Deliberation Number 85 1 March 2012). Demographic characteristics and medical history (with specific reference to renal disease), both at referral (baseline) and during follow-up, and information on new renal events were collected. CKD was classified according to the KDIGO guidelines (11Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int. Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1013) Google Scholar). Estimated glomerular filtration rate (eGFR) was calculated using the 2009 CKD-EPI creatinine equation (12Levey A.S. Stevens L.A. Schmid C.H. Zhang Y.L. Castro III, A.F. Feldman H.I. Kusek J.W. Eggers P. Van Lente F. Greene T. et al.CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)A new equation to estimate glomerular filtration rate.Ann. Intern. Med. 2009; 150: 604-612Crossref PubMed Scopus (12552) Google Scholar). The follow-up period was defined as the time between the first and the last available contact. The mean follow-up was 12 ± 8.5 years (range: 1–24 years). Event of interest was defined as any of the following: 1) dialysis, 2) kidney transplantation, or 3) death for renal complications. Blood samples were collected after an overnight fast and plasma separated by low-speed centrifugation at 4°C. Plasma total cholesterol, HDL-cholesterol, triglyceride, and apolipoprotein levels were determined with certified methods using a Roche Integra c311 autoanalyzer (Roche Diagnostics). LDL-cholesterol was calculated using the Friedewald's formula. When triglycerides were >400 mg/dl (two cases), LDL-cholesterol was assessed using direct measurement. LDL-cholesterol levels were virtually identical when calculated by the Martin-Hopkins equation compared with the Friedewald's formula (91.8 ± 61.0 mg/dl and 91.7 ± 61.0 mg/dl, respectively). Unesterified cholesterol was determined by using a previously described enzymatic technique (13Gomaraschi M. Ossoli A. Castelnuovo S. Simonelli S. Pavanello C. Balzarotti G. Arca M. Di Costanzo A. Sampietro T. Vaudo G. et al.Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency.J. Lipid Res. 2017; 58: 994-1001Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). Plasma LCAT concentration was measured by a specific competitive enzyme-linked immunoassay (14Murakami T. Michelagnoli S. Longhi R. Gianfranceschi G. Pazzucconi F. Calabresi L. Sirtori C.R. Franceschini G. Triglycerides are major determinants of cholesterol esterification/transfer and HDL remodeling in human plasma.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1819-1828Crossref PubMed Scopus (158) Google Scholar). Plasma cholesterol esterification rate and LCAT activity, which reflect the ability of endogenous LCAT to esterify cholesterol within endogenous lipoproteins and exogenous HDL, respectively, were assessed by using previously described methods (2Calabresi L. Pisciotta L. Costantin A. Frigerio I. Eberini I. Alessandrini P. Arca M. Bon G.B. Boscutti G. Busnach G. et al.The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1972-1978Crossref PubMed Scopus (128) Google Scholar). The presence of proteinuria was assessed by protein reagent strip and then confirmed by spot test and/or 24 h urine collection. Descriptive statistics such as mean ± SD were estimated for all variables. Comparisons between groups were performed by independent t-test or Chi-square as appropriate. Nonnormally distributed variables were log-transformed before proceeding to the analysis. We estimated the time to first renal event by using Kaplan-Meier survival curves. Survival curves stratified by sex and median unesterified cholesterol were compared by using the log-rank test. Due to the limited sample size, no adjusted analyses were carried out (15D'Erasmo L. Minicocci I. Nicolucci A. Pintus P. Roeters Van Lennep J.E. Masana L. Mata P. Sánchez-Hernández R.M. Prieto-Matos P. Real J.T. et al.Autosomal recessive hypercholesterolemia: long-term cardiovascular outcomes.J. Am. Coll. Cardiol. 2018; 71: 279-288Crossref PubMed Scopus (19) Google Scholar). All statistical analyses were performed using SPSS software version 26.0 (SPSS Inc., Chicago, IL). Tests were two-sided and P values <0.05 were considered as statistically significant. Eighteen Caucasian subjects (6 females and 12 males) with molecular confirmation of FLD were included in the analysis. Included subjects were either homozygous or compound heterozygous carriers of mutations in the LCAT gene. FLD cohort characteristics at diagnosis are summarized in Table 1. Median age at diagnosis was 32.5 years (range: 20–70 years); twelve were male. FLD patients showed the typical lipid profile, characterized by very low HDL-cholesterol, ApoA-I, and ApoA-II levels, and high triglycerides. As expected in the total absence of LCAT activity, assayed on both exogenous and endogenous lipoproteins (LCAT activity and cholesterol esterification rate, respectively), plasma cholesterol was mainly unesterified, although with a certain variability. Included cases carried 15 different mutations in the LCAT gene and belonged to 14 families. No major differences were observed between females and males, except for a significantly higher prevalence of hypertension in males.TABLE 1Demographic and lipid/lipoprotein characteristics of FLD patients at diagnosisAll (n = 18)Females (n = 6)Males (n = 12)Reference ValuesAge at diagnosis (years)37.5 ± 14.838.2 ± 15.137.2 ± 15.3—Body mass index (kg/m2)23.8 ± 3.021.9 ± 2.724.2 ± 3.118–25Total cholesterol (mg/dl)156.1 ± 81.4134.3 ± 61.1168 ± 91.0<200Unesterified cholesterol (mg/dl)140.1 ± 73.2113.7 ± 45.8154.5 ± 82.9<60Unesterified/total cholesterol0.91 ± 0.110.86 ± 0.100.94 ± 0.11<0.30LDL-cholesterol (mg/dl)91.7 ± 61.068.8 ± 23.8104.2 ± 72.0<130HDL-cholesterol (mg/dl)7.2 ± 3.47.5 ± 3.37.1 ± 3.5>40Triglycerides (mg/dl)266.9 ± 179.1282.2 ± 209258.5 ± 170.8<150Phospholipids (mg/dl)292.6 ± 118.0261.2 ± 79.2306.9 ± 133.0<200ApoA-I (mg/dl)36.4 ± 8.831.7 ± 6.138.9 ± 133.0115–180ApoA-II (mg/dl)6.9 ± 4.08.1 ± 6.16.6 ± 3.626–51ApoB (mg/dl)50.7 ± 26.960 ± 23.844.6 ± 28.370–150LCAT mass (µg/ml)1.55 ± 1.382.35 ± 1.761.06 ± 0.863.1–6.7Cholesterol esterification rate (nmol/ml/h)0 ± 00 ± 00 ± 030–60LCAT activity (nmol/ml/h)0 ± 00 ± 00 ± 025–55Hemoglobin (g/dl)10.2 ± 2.110.7 ± 1.59.9 ± 2.6>12Presence of proteinuria [yes, n (%)]7 (38)2 (33)5 (42)AbsentHypertension [yes, n (%)]12 (67)1 (17)11 (92)aP < 0.05 versus females.NoData are reported as mean ± SD or number (%).a P < 0.05 versus females. Open table in a new tab Data are reported as mean ± SD or number (%). Twelve FLD patients (three females and nine males, mean age 41.7 ± 15.0 years) already had CKD at diagnosis; seven had proteinuria (moderately to severely increased), four were on hemodialysis, and one already had kidney transplantation. Mean eGFR in these patients was 36.2 ± 36.4 ml/min/1.73 m2. The remaining patients (three females and males) had renal function at diagnosis ± ml/min/1.73 and absence of and were age ± years). of eGFR time for one patient with renal function and one patient with proteinuria was reported in unesterified cholesterol was higher in FLD patients with CKD at diagnosis ± mg/dl ± of renoprotective agents at diagnosis was in seven Mean follow-up was 12 ± 8.5 years (range: 1–24 years). follow-up, renal events kidney or death for renal were an of events of new events were observed in FLD patients with renal function at Survival was performed to the median age of of any renal dialysis, kidney transplantation, or death for renal Kaplan-Meier survival analyses showed that the median survival in the FLD cohort was 46 years patients had a second kidney failure caused by the disease confirmed by renal that dialysis, and a second kidney Kaplan-Meier for event recurrence showed that median time to a second event kidney or death for renal was 10 years the decade of of FLD patients had CKD or were Survival curves for sex showed that survival time was in females compared with males time years in females and males, respectively), although it not statistical P = 2) and a of hypertension not However, Kaplan-Meier survival analyses showed in this hypertension was not with renal events when subjects were according to unesterified cholesterol or median plasma levels at diagnosis survival was significantly in patients with unesterified cholesterol values the median time years for unesterified cholesterol and the log-rank P = A was performed by curves stratified for unesterified cholesterol level after including only subjects of the The log-rank test was that a by hypertension is of FLD corneal opacification, which represents a of the disease but is with hemolytic anemia, and renal Renal disease represents the major cause of morbidity and mortality in FLD proteinuria can develop early in life and can unpredictably to renal insufficiency and eventually to renal Due to the of the disease, the history of FLD is In the years, we have collected a large cohort of carriers of LCAT which unrelated families. to the of a large number of FLD followed in cases for two we showed that of the FLD patients had the first renal kidney failure or kidney or death for renal by the age of 46 years. we showed that median time to a second kidney failure, kidney or death for renal was 10 years, and by the decade of age of FLD patients had CKD or were and of renal damage in FLD patients is within the (2Calabresi L. Pisciotta L. Costantin A. Frigerio I. Eberini I. Alessandrini P. Arca M. Bon G.B. Boscutti G. Busnach G. et al.The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1972-1978Crossref PubMed Scopus (128) Google Scholar), that genetic and can on kidney The biochemical which is in FLD patients, on such as A. M. L. R. J. of a new LCAT causing familial LCAT deficiency (FLD) and the of as a gene of the FLD 2009; Full Text Full Text PDF PubMed Scopus Google Scholar), is a major of kidney failure I. F. F. M. R. A. Lipid the LCAT renal disease in familial LCAT deficiency.J. Med. Crossref Google Scholar). The of lipids in renal damage is by the of in the S. Zhang B. S. of renal in patients with lecithin:cholesterol acyltransferase deficiency by in Thromb. Vasc. Biol. PubMed Scopus Google and by the in of abnormal lipoprotein of and unesterified cholesterol (3Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer H.B.J. Lecithin cholesterol acyltransferase deficiency and fish eye disease.in: Scriver C.R. Beaudet A.L. Sly W.S. The Metabolic and Molecular Bases of Inherited Diseases. McGraw-Hill, New York2001: 2817-2833Google Scholar). in unesterified cholesterol level at diagnosis was the only plasma lipid to identify patients with rapid deterioration of kidney function. unesterified cholesterol plasma level is the leading of LCAT the unesterified cholesterol in lipoproteins and it in the abnormal a or a comprised of an been shown to and in and metabolism of in PubMed Scopus (19) Google Scholar), it in the kidney and for the lipid in one of the findings in the of FLD patients (3Santamarina-Fojo S. Hoeg J.M. Assmann G. Brewer H.B.J. Lecithin cholesterol acyltransferase deficiency and fish eye disease.in: Scriver C.R. Beaudet A.L. Sly W.S. The Metabolic and Molecular Bases of Inherited Diseases. McGraw-Hill, New York2001: 2817-2833Google Scholar). Renal represents an in severe FLD cases with kidney not correct the enzymatic disease can rapidly As for other characterized by renal life but graft survival is limited A. L. S. J.M. G. V. A. of kidney in Int. Full Text Full Text PDF PubMed Scopus Google Scholar). in cohort of 18 FLD patients, 5 had a second renal failure that dialysis, and a second kidney within 15 years. The of FLD on the and on the of the unesterified with to LCAT activity and eventually unesterified cholesterol, is an and it is clinical R. R. M.J. Freeman L.A. Familial lecithin:cholesterol acyltransferase deficiency: treatment with 2016; Full Text Full Text PDF PubMed Scopus Google Scholar, R. Freeman L.A. M.J. B. R. S.J. et and of a human lecithin:cholesterol in a 1 Res. 2016; PubMed Scopus Google Scholar). A second is by gene M.J. Vaisman B. B. Jr., S. Brewer Jr., of human lecithin-cholesterol acyltransferase in to an lipoprotein by lipoprotein and 2009; 58: Full Text Full Text PDF PubMed Scopus Google Scholar), which is at present very from in of eventually have been in and to to not only but LCAT L.A. Demosky Jr., S.J. M. R. A. Ossoli A.F. M. et acyltransferase by of 2017; PubMed Scopus Google Scholar). In conclusion, the present study highlights the severe consequences of FLD, which to kidney failure before the decade of and the need of early diagnosis and referral to specialized centers, and the urgency for effective treatments to prevent or slow the renal disease in FLD The and/or during the study are available from Calabresi with chronic kidney disease estimated glomerular filtration rate familial LCAT deficiency lipoprotein X

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