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

Abstract

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.

Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux

“…To examine the levels and profile of HDL species, equal volumes of serum samples were separated by denaturant and native PAGE and analyzed by western blot for ApoA-I protein content by using anti-human ApoA-I antibodies. Serum from L75P heterozygotic patients presented lower amounts of total ApoA-I protein (33 % reduction compared to control subjects, Figure 1A), which agrees with previous reports 16,17,20 , whereas ApoA-I levels in serum of L174S patients were similar to those of control subjects. Analysis of the samples by native western blot supported this observation and also revealed differences in the distribution of HDL species (Figure 1B).…”

Molecular basis for a novel systemic form of human hereditary apoA-I amyloidosis with vision loss

“…Clinical and pathological renal features of three additional Glu34Lys patients described in the current study definitively establish the causal role of Glu34Lys apoA-I in glomerular amyloid deposition. This new renal presentation contrasts with the typical tubulo-interstitial nephritis described previously for other apoA-I variants, which manifested as a slowly progressing, non-proteinuric renal failure with amyloid deposition restricted to the renal medulla (Gregorini et al, 2005;Gregorini et al, 2015). We conclude that AApoAI is characterized by distinct renal patterns of amyloid which depend on the nature of the apoA-I variant.…”

Characterization of circulating APOL1 protein complexes in African Americans

“…APOL1 ( 5 ), APOA1, and HPR proteins are present in renal tubule cells, but not glomeruli, whereas HPR and APOA1 mRNAs are absent in glomeruli (data not shown). It is possible that circulating APOL1 complexes/TLFs are catabolized by renal tubule cells ( 34 ), instead of being directly involved in glomerulosclerosis, as we originally hypothesized. Although our results do not support a role for the APOL1 complexes in the pathogenesis of glomerulosclerosis due to the absence of APOA1 and HPR (mRNAs and proteins), the key components of APOL1 complexes (TLF1 and TLF2), in glomeruli, they clarify the perspective that locally synthesized APOL1 in the kidney, especially in glomerular podocytes, is the major player of focal glomerulosclerosis .…”