Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia-Brief Report.

OBJECTIVE: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? APPROACH AND RESULTS: Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. CONCLUSIONS: PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.

Kidney post-transplant monitoring of urinary glycosaminoglycans/proteoglycans and monokine induced by IFN-γ (MIG).

Allograft rejection during the first year after renal transplantation can lead to persistent allograft dysfunction and reduced long-term graft survival. Thus, it is important to define early predictors of kidney damage, less invasive than allograft biopsy. Urinary glycosaminoglycan/proteoglycan concentration and distribution, N-acetyl-ß-(D)-glucosaminidase (NAG), and monokine induced by IFN-γ (MIG) levels were evaluated in the immediate post-transplant and during a 1-year follow-up. We observed increased urinary levels of MIG, urinary trypsin inhibitor and its degradation products, the lack of urinary heparan sulfate excretion, and the decreased chondroitin sulfate relative content at day 1 post-transplant in most patients who developed complications in the postoperative period. Moreover, urinary MIG levels showed significant correlations with NAG, C-reactive protein, and GFR at day 1 post-transplant. The monitoring of glycosaminoglycan/proteoglycan urinary pattern and the levels of urine MIG could serve as useful markers for predicting possible complications of transplantation, unraveling an early inflammatory state, on whose basis the immunosuppressive therapy could be appropriately modified.

[Lyell's syndrome: proposal for a therapeutic protocol]. / Sindrome di Lyell: proposta di un protocollo terapeutico.

Toxic epidermal necrolysis or Lyell's syndrome is a life-threatening, drug-induced disorder characterized by severe epidermal injury. Although plasmapheresis is expensive and requires easy venous access, it could be included in the first-line treatment of toxic epidermal necrolysis. The method is safe and effective, providing prompt relief from pain and rapid cessation of necrolysis. Moreover, in our experience plasmapheresis could be used in patients who were unresponsive to corticosteroids, and in patients with severe clinical symptoms.

[LDL-apheresis in patients with familial autosomal recessive hypercholesterolemia]. / LDL aferesi nella Ipercolesterolemia Autosomica Recessiva (ARH).

LDL-apheresis reduces the cardiovascular risk in patients with familial hypercholesterolemia. The addition of statin therapy in patients with autosomal recessive hypercholesterolemia may change the lipid profile to a less atherogenic pattern.

Linkage Analysis: An Important Tool for Pre-Clinical Alport's Diagnosis.

The phenotypic heterogeneity of Alport's syndrome (AS) is well explained by the genetic heterogeneity. Therefore, the application of genetic techniques, such as linkage analysis (LA), could be helpful in the correct diagnosis of this disease. We performed LA in a family who manifested X-linked inheritance. We used 10 fluorescent microsatellite markers to cover the q-arms of chromosome X. The poly chain reaction (PCR) products were separated on an ABI 377 Sequencer and genotypes were identified using the ABI Genescan/Genotyper software. We confirm in this family an X-linked dominant transmission of AS. All affected individuals shared the same haplotype for the region Xq22. The genetic diagnosis of AS was confirmed in individuals aged one month and 4 years before any clinical manifestation of AS. We conclude that LA is a powerful and approachable tool, which could be used in the diagnosis of AS. An accurate genetic family study using LA may be helpful for correct classification, genetic counseling, prognosis evaluation, the assessment of the risk for kidney transplantation, and for the follow-up and therapy of AS.