Tubulointerstitial nephritis is a dominant feature of hereditary apolipoprotein A-I amyloidosis.

Apolipoprotein A-I is the main protein of high-density lipoprotein particles, and is encoded by the APOA1 gene. Several APOA1 mutations have been found, either affecting the lecithin:cholesterol acyltransferase activity, determining familial HDL deficiency, or resulting in amyloid formation with prevalent deposits in the kidney and liver. Evaluation of familial tubulointerstitial nephritis in patients with the Leu75Pro APOA-I amyloidosis mutation resulted in the identification of 253 carriers belonging to 50 families from Brescia, Italy. A total of 219 mutation carriers underwent clinical, laboratory, and instrumental tests. Of these, 62% had renal, hepatic, and testicular disease; 38% were asymptomatic. The disease showed an age-dependent penetrance. Tubulointerstitial nephritis was diagnosed in 49% of the carriers, 13% of whom progressed to kidney failure requiring dialysis. Hepatic involvement with elevation of cholestasis indices was diagnosed in 30% of the carriers, 38% of whom developed portal hypertension. Impaired spermatogenesis and hypogonadism was found in 68% of male carriers. The cholesterol levels were lower than normal in 80% of the mutation carriers. Thus, tubulointerstitial nephritis was highly prevalent in this large series of patients with Leu75Pro apoA-I amyloidosis. Persistent elevation of alkaline phosphatase, reduced HDL cholesterol plasma levels, and hypogonadism in men are key diagnostic features of this form of amyloidosis.

Vascular alterations in apolipoprotein A-I amyloidosis (Leu75Pro). A case-control study.

BACKGROUND: Among hereditary amyloidoses, apolipoprotein A-I (APO A-I) amyloidosis (Leu75Pro) is a rare, autosomal dominant condition in which renal, hepatic, and testicular involvement has been demonstrated. OBJECTIVE: To investigate vascular structural as well as functional alterations. METHODS: In 131 carriers of the amyloidogenic Leu75Pro APO A-I mutation (mean age 52 + 16 years, 56 women) and in 131 subjects matched for age, sex, body mass index and clinic blood pressure (BP), arterial stiffness (pulse wave velocity, PWV) and carotid intima-media thickness (IMT) were measured. RESULTS: By definition no differences for age, sex, body mass index, and BP were observed. Meanmax IMT (Mmax-IMT) in the common (CC), bifurcation (BIF) and internal (ICA) carotid artery were comparable in the two groups. After adjustment for high-density lipoprotein cholesterol and renal function differences between the two groups, a lower meanmax-IMT was observed in APO A-I Leu75Pro mutation carriers than in controls (CC Mmax-IMT 0.87 ± 0.21 versus 0.93 ± 0.2 mm, p = 0.07; BIF Mmax-IMT 1.19 ± 0.48 versus 1.36 ± 0.46 mm, p = 0.025; ICA Mmax-IMT 0.9 ± 0.37 versus 1.02 ± 0.35 mm, p = 0.028). On the other hand, aortic stiffness was significantly greater in patients with APO A-I amyloidosis than controls (PWV 11.5 ± 2.9 and 10.7 ± 2.3 m/s, p < 0.05), even after adjusting for confounders. CONCLUSIONS: In carriers of the amyloidogenic Leu75Pro APO A-I mutation, a significant increase in arterial stiffness is observed; on the contrary, carotid artery IMT is comparable to that of control subjects. These results may add significant information to the clinical features of this rare genetic disorder.

Effect of the amyloidogenic L75P apolipoprotein A-I variant on HDL subpopulations.

BACKGROUND: Hereditary amyloidosis due to mutations of apolipoprotein A-I (apoA-I) is a rare disease characterized by the deposition of amyloid fibrils constituted by the N-terminal fragment of apoA-I in several organs. L75P is a variant of apoA-I associated with systemic amyloidosis predominantly involving the liver, kidneys, and testis, identified in a large number of unrelated subjects. Objective of the present paper was to evaluate the impact of the L75P apoA-I variant on HDL subpopulations and cholesterol esterification in carriers. METHODS AND RESULTS: Plasma samples were collected from 30 carriers of the amyloidogenic L75P apoA-I (Carriers) and from 15 non affected relatives (Controls). Carriers displayed significantly reduced plasma levels of HDL-cholesterol, apoA-I, and apoA-II compared to Controls. Plasma levels of LpA-I, but not LpA-I:A-II, were significantly reduced in Carriers. HDL subclass distribution was not affected by the presence of the variant. The unesterified to total cholesterol ratio was higher, and cholesterol esterification rate and LCAT activity were lower in Carriers than in Controls. CONCLUSIONS: The L75P apoA-I variant is associated with hypoalphalipoproteinemia, a selective reduction of LpA-I particles, and a partial defect in cholesterol esterification.