Early Left Ventricular Global Longitudinal Strain Deterioration After Aortic Aneurysm Repair: Impact of Aortic Stiffness.

PURPOSE: To associate the impact of aortic reconstruction using currently available grafts and endografts on pulse wave velocity in patients with abdominal aortic aneurysm (AAA) and to evaluate its effect on early cardiac systolic function indices. MATERIALS AND METHODS: Seventy-three consecutive patients with AAA (mean age 70±8 years; all men) who underwent open (n=12) or endovascular repair (EVAR; n=61) were prospectively enrolled in an observational cohort study. Left ventricular global longitudinal strain (GLS; an important diagnostic and prognostic index of early systolic dysfunction) and carotid-femoral pulse wave velocity (cf-PWV) were estimated 1 week preoperatively, as well as at 1 and 6 months postoperatively. RESULTS: A significant time effect was found for cf-PWV, which showed an increase at 1 month that remained through 6 months (p=0.007). Additionally, a deterioration in GLS values was revealed, with a significant change at 1 month that persisted 6 months later (p<0.001). No significant group effect was observed between EVAR and open repair (p=0.98), and there was no significant interaction (p=0.96). Notably, the difference in GLS between baseline and 6 months significantly correlated with the corresponding changes in cf-PWV (r=0.494, p<0.001). CONCLUSION: AAA repair leads not only to an increase in aortic stiffness, as measured by the increase in pulse wave velocity, but also to reduced cardiac systolic function. Our findings highlight the need for a more intense cardiac surveillance program after aortic reconstruction. Further studies are needed to investigate how this may translate into long-term manifestations of cardiovascular complications and symptomatology.

Intense immunostaining of heat shock protein 70 within renal interstitium associates with long-term renal survival in an ANCA-associated vasculitis cohort.

In anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) genetic predisposition, ANCA autoantibodies, neutrophil extracellular traps (NETs), complement activation, and toll-like receptor signaling are implicated in AAV pathogenesis. Heat shock proteins (HSPs), a highly conserved group of small-sized molecular chaperones, take part in protein folding during cellular stress. Although HSPs were initially observed intracellularly, it has been shown that they can be secreted in the extracellular space and modulate the immune response in various autoimmune diseases including AAV. The scope of the present study is to investigate the role of heat shock protein 60 (HSP60) and 70 (HSP70) in the long renal effects in an ANCA vasculitis cohort. In this cohort of ANCA-associated vasculitis, 29 patients were followed up over 20 years. At diagnosis, immunohistochemistry was performed for HSP60 and HSP70 within the various nephron compartments. Higher renal HSP60 expression was associated with increased interstitial inflammatory infiltrates at diagnosis, while HSP70 expression was associated with a greater extent of interstitial fibrosis at diagnosis. Notably, intense tissue expression of HSP70 at the time of biopsy was associated with a worsened kidney survival. Renal HSP70 expression was associated with poor renal outcomes during long-term follow-up. This finding may indicate a role of HSPs in renal disease progression in ANCA vasculitis. Further validating studies are needed to verify a causative association between HSP70 expression and renal outcomes in ANCA-associated vasculitis.

Current Concepts on the Reno-Protective Effects of Phosphodiesterase 5 Inhibitors in Acute Kidney Injury: Systematic Search and Review.

Acute kidney injury (AKI) is associated with increased morbidity, prolonged hospitalization, and mortality, especially in high risk patients. Phosphodiesterase 5 inhibitors (PDE5Is), currently available as first-line therapy of erectile dysfunction in humans, have shown a beneficial potential of reno-protection through various reno-protective mechanisms. The aim of this work is to provide a comprehensive overview of the available literature on the reno-protective properties of PDE5Is in the various forms of AKI. Medline was systematically searched from 1946 to November 2019 to detect all relevant animal and human studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. In total, 83 studies were included for qualitative synthesis. Sildenafil is the most widely investigated compound (42 studies), followed by tadalafil (20 studies), icariin (10 studies), vardenafil (7 studies), zaprinast (4 studies), and udenafil (2 studies). Even though data are limited, especially in humans with inconclusive or negative results of only two clinically relevant studies available at present, the results of animal studies are promising. The reno-protective action of PDE5Is was evident in the vast majority of studies, independently of the AKI type and the agent applied. PDE5Is appear to improve the renal functional/histopathological alternations of AKI through various mechanisms, mainly by affecting regional hemodynamics, cell expression, and mitochondrial response to oxidative stress and inflammation.

Microsomal triglyceride transfer protein inhibitor (lomitapide) efficacy in the treatment of patients with homozygous familial hypercholesterolaemia.

AIMS: The aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor (lomitapide) in patients with homozygous familial hypercholesterolaemia. METHODS AND RESULTS: In 12 homozygous familial hypercholesterolaemia patients treated with lipid-lowering drugs ± biweekly lipoprotein apheresis sessions (nine patients), daily lomitapide was added. The lipid profile (total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol) before and after lomitapide treatment was evaluated. The follow-up period with lomitapide treatment was 3-24 months (13.8 ± 7.9). The median baseline low-density lipoprotein cholesterol level was 900 mg/dl (348-1070), after lipid-lowering drugs therapy was 383.5 mg/dl (214-866) and after lipid-lowering drugs + time-averaged level was 288 mg/dl (183.7-716.6). The addition of lomitapide lowered low-density lipoprotein cholesterol levels further by 56.8% compared to lipid-lowering drugs alone (mean reduction 262, 95% confidence interval (105.5-418.7), p = 0.005) and by 54% (mean reduction 182.9, 95% confidence interval (-342 - -23), p = 0.031) comparing to lipid-lowering drugs + lipoprotein apheresis (time-averaged level). The time-averaged level of low-density lipoprotein cholesterol in lipid-lowering drugs + lipoprotein apheresis patients compared with lipid-lowering drugs + lomitapide was 54% in favour of lomitapide (p = 0.031). CONCLUSIONS: Treatment with lomitapide in homozygous familial hypercholesterolaemia patients has a beneficial effect with a constant decrease of low-density lipoprotein cholesterol by 57% compared with classical lipid-lowering therapy and by 54% compared with classical lipid-lowering therapy and time-averaged level of low-density lipoprotein cholesterol.

The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred.

RATIONALE & OBJECTIVE: Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied. PREDICTORS: Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants. OUTCOMES: Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate. ANALYTICAL APPROACH: Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis. RESULTS: 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and "foam-cell" infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of 3.56 mL/min/1.73 m2. The incidence of cardiovascular and renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants. LIMITATIONS: The presence of cardiovascular disease was mainly based on medical history. CONCLUSIONS: The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis.

Renal artery stenting for atherosclerotic renal artery stenosis identified in patients with coronary artery disease: Does captopril renal scintigraphy predict outcomes?

The authors evaluated the effectiveness of percutaneous renal revascularization (PRR) with stenting for the treatment of atherosclerotic renal artery stenosis (ARAS) in patients with coronary artery disease and the usefulness of captopril renal scintigraphy for predicting clinical outcomes after PRR. Sixty-four consecutive patients, referred for evaluation of suspected ARAS, after coronary angiography, underwent baseline captopril renal scintigraphy followed by renal angiography. Forty-four patients (68.7%) were diagnosed with a significant ARAS≥ 60% and were treated with PRR plus medical therapy. Twenty-four months after PRR, 86.4% and 73.3% of patients showed a hypertension and renal benefit, respectively. Captopril renal scintigraphy positivity had moderate sensitivity and high specificity in predicting a hypertension and renal benefit. In patients with ARAS≥ 70%, the sensitivity and specificity were 100% for both a hypertension and renal benefit.PRR for ARAS conferred a substantial benefit in patients with a high coronary artery disease burden. Captopril renal scintigraphy was highly accurate in predicting clinical outcomes.

Acute Interstitial Nephritis and Membranous Nephropathy in the Context of IgG4-Related Disease.

We present the case of a patient with IgG4-related disease, which manifested in an asynchronous manner as vitiligo, cholecystitis, sialadenitis, lymphadenopathy, facial palsy and kidney dysfunction. The patient underwent a renal biopsy, and a presumptive diagnosis of lupus nephritis was made due to compatible clinical and immunological findings. The biopsy revealed IgG4-related kidney disease with severe interstitial nephritis and membranous nephropathy. Corticosteroids treatment restored all disease manifestations. We bring this case to the attention of the nephrologists because of the protean, asynchronous, multisystemic nature of the disease that necessitates a multidisciplinary approach, a low threshold for kidney biopsy and a high index of suspicion for making the correct diagnosis and treatment.

Rapamycin ameliorates proteinuria and restores nephrin and podocin expression in experimental membranous nephropathy.

OBJECTIVE: Recent studies have shown a beneficial effect of rapamycin in passive and active Heymann Nephritis (HN). However, the mechanisms underlying this beneficial effect have not been elucidated. METHODS: Passive Heymann Nephritis (PHN) was induced by a single intravenous infusion of anti-Fx1 in 12 Sprague-Dawley male rats. One week later, six of these rats were commenced on daily treatment with subcutaneous rapamycin 0.5 mgr/kg (PHN-Rapa). The remaining six rats were used as the proteinuric control group (PHN) while six more rats without PHN were given the rapamycin solvent and served as the healthy control group (HC). All rats were sacrificed at the end of the 7th week. RESULTS: Rapamycin significantly reduced proteinuria during the autologous phase of PHN. Histological lesions were markedly improved by rapamycin. Immunofluorescence revealed attenuated deposits of autologous alloantibodies in treated rats. Untreated rats showed decreased glomerular content of both nephrin and podocin whereas rapamycin restored their expression. CONCLUSIONS: Rapamycin monotherapy significantly improves proteinuria and histological lesions in experimental membranous nephropathy. This beneficial effect may be mediated by inhibition of the alloimmune response during the autologous phase of PHN and by restoration of the normal expression of the podocyte proteins nephrin and podocin.

Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice.

BACKGROUND: In the normal kidney, rapamycin is considered to be non-nephrotoxic. In the present study, we investigated whether rapamycin is indeed non-nephrotoxic by examining the ultrastructural and molecular alterations of podocytes in healthy mice. METHODS: Balb/c mice were given three different intraperitoneal doses of rapamycin for 1 week (dose model)-low-dose group: 1 mg/kg/day, intermediate-dose (ID) group: 1.5 mg/kg/day and high-dose (HD) group: 3 mg/kg/day; four mice in each group. An ID of rapamycin was also given for three different periods (time model): 1, 4 and 8 weeks; four mice were in each group. Mice treated with dimethyl sulphoxide served as controls. Body weight was measured weekly. Renal function was assessed by serum creatinine at the time of sacrifice. For estimation of albuminuria, 24-h urine collections were performed before treatment and weekly thereafter. Glomerular content of nephrin, podocin, Akt and Ser473-phospho-Akt was estimated by western blot and immunofluorescence. Nephrin and podocin messenger RNA (mRNA) were measured by real-time polymerase chain reaction. Mean podocyte foot process width (FPW) was measured by electron microscopy. RESULTS: Urine albumin levels increased in the HD and 4-week groups. Renal function was modestly deteriorated in the HD group. The mean FPW increased in a dose-dependant manner at Week 1, further deteriorated at Week 4 and finally improved at Week 8. Nephrin and podocin mRNA levels showed a significant decrease at Week 1 and were restored at Week 4 and 8. Nephrin and podocin protein levels were reduced at Week 4 and recovered at Week 8. Ser473-phospho-Akt significantly increased in all rapamycin-treated groups. CONCLUSIONS: Rapamycin induced significant ultrastructural and molecular alterations in podocytes in association with albuminuria. These alterations happened early during treatment and they tended to improve over an 8-week treatment period.

The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin.

BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor, rapamycin, has been shown to inhibit the progression of murine lupus nephritis by virtue of its potent immunosuppressive properties. The phosphoinositol-3-kinase (PI3K)/Akt pathway is a major upstream activator of mTOR and has been implicated in the propagation of cancer and autoimmunity. However, the activation status of the PI3K/Akt/mTOR pathway in lupus nephritis has not been studied so far. METHODS: In NZBW/F1 female mice, we examined the glomerular expression of Akt and mTOR by immunofluorescence and western blot. We also searched for specific phosphorylations of these kinases known to ensue during activation of the PI3K/Akt/mTOR pathway. In parallel, we examined the therapeutic role of rapamycin either before or after the development of overt lupus nephritis. RESULTS: We found that in untreated mice, as opposed to healthy controls, Akt and mTOR were over-expressed and phosphorylated at key activating residues. Rapamycin prolonged survival, maintained normal renal function, normalized proteinuria, restored nephrin and podocin levels, reduced anti-dsDNA titres, ameliorated histological lesions, and reduced Akt and mTOR glomerular expression activation. CONCLUSIONS: These results suggest that: (i) the PI3K/Akt/mTOR pathway is upregulated in murine lupus nephritis, thus justifying treatment with rapamycin; (ii) rapamycin not only blocks mTOR but also negatively regulates the PI3K/Akt/mTOR pathway; and (iii) rapamycin is an effective treatment of murine lupus nephritis. Examination of the PI3K/Akt/mTOR pathway may offer new insights into the pathogenesis of lupus nephritis in humans and may lead to more individualized and less toxic treatment.

Membranous nephropathy and lupus-like syndrome after hematopoietic cell transplantation: a case report.

INTRODUCTION: The kidney is increasingly recognised as a target organ of chronic graft-versus-host disease after hematopoietic cell transplantation in the context of the development of the nephrotic syndrome. Chronic graft-versus-host disease is associated with autoimmune phenomena similar, but not identical, to those observed in various rheumatologic disorders, implicating autoimmunity as an important component of the disease. CASE PRESENTATION: We report the case of a 57-year-old Caucasian man who developed the nephrotic syndrome due to membranous nephropathy in association with recurrent chronic graft-versus-host disease, along with a lupus-like syndrome manifested with pancytopenia, hair loss, positive anti-DNA antibodies and sub-epithelial and mesangial immune deposits. To the best of our knowledge, this is the first case reported in the literature. The nephrotic syndrome subsided soon after he was treated with a short course of cyclosporin with steroids. Unfortunately he died seven months later due to a relapse of leukemia. CONCLUSIONS: Our case report confirms the notion that chronic graft-versus-host disease is characterized by the appearance of autoimmune phenomena similar, but not identical, to those seen in autoimmune diseases. The decision for more immunosuppression has to be weighed against the need for preservation of the graft versus leukemia phenomenon.

Biopsy-proven resolution of renal light-chain deposition disease after autologous stem cell transplantation.

Light-chain deposition disease (LCDD) is caused by an underlying clonal plasma cell dyscrasia in which monoclonal immunoglobulin light chains (LCs) are deposited in tissues, resulting in varying degrees of organ dysfunction. Autologous stem cell transplantation (ASCT) has been reported to stabilize renal function in patients with LCDD, but currently, no evidence of histopathologic resolution of LC deposition after ASCT exists. We present a patient, with severe renal dysfunction due to LCDD, who was treated with high-dose melphalan and ASCT that resulted in a significant and extended period of improved renal function. Four years after the initial improvement, the patient developed nephrotic range proteinuria, without any evidence of relapse of the plasma cell dyscrasia. At that time, a repeat renal biopsy showed complete resolution of LC depositions and development of extensive glomerulosclerosis, thus explaining proteinuria. To the best of our knowledge, this is the first report of a biopsy-proven resolution of renal LCDD following ASCT. A timely application of ASCT should be considered in LCDD to prevent deterioration of renal function in the long run.