Ten-year experience of an outpatient clinic for CKD-5 patients with multidisciplinary team and educational support.

PURPOSE: To analyze the results of an outpatient clinic with a multidisciplinary team and educational support for patients with late-stage CKD (lsCKD), to check its possible effect on their outcomes. METHODS: Longitudinal cohort study on patients followed up in the MaReA (Malattia Renale Avanzata = CKD5) outpatient clinic at ASST Spedali Civili of Brescia from 2005 to 2015 for at least six months. Trajectory of renal function over time has been evaluated only in those patients with at least four estimations of eGFR before referring to MaReA. RESULTS: Seven hundred and six patients were enrolled, their mean age was 72 ± 14 years, 59% were males. At the end of the study, 147 (21%) were still on MaReA, 240 (34%) on dialysis, 92 (13%) on very low-protein diet (VLPDs), 13 (2%) on pre-hemodialysis clinic, 23 (3%) improved renal function, 10 (1%) transplanted, 62 (9%) transferred/lost to follow-up, and 119 (17%) died. Optimal dialysis start (defined as start with definitive dialysis access, as an out-patient and without lsCKD complications) occurred in 180/240 (75%) patients. The results showed a slower eGFR decrease during MaReA follow-up compared to previous renal follow-up: - 2.0 vs. - 4.0 mL/min/1.73 m2 BSA/year (p < 0.05), corresponding to a median delay of 17.7 months in dialysis start in reference to our policy in starting dialysis. The patient cumulative survival was 75% after 24 months and 25% after 70. LIMITATIONS: (1) lack of a control group, (2) one-center-study, (3) about all patients were Caucasians. CONCLUSION: The follow-up of lsCKD patients on MaReA is associated with an optimal and delayed initiation of dialysis.

Kidney transplant patients with SARS-CoV-2 infection: The Brescia Renal COVID task force experience.

The outcome of kidney transplant patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still unclear. Here we describe the clinical characteristics, disease outcome, and risk factors for acute respiratory distress syndrome (ARDS) and death of a cohort of 53 kidney transplant patients with coronavirus disease 2019 (COVID-19). Eight of 53 have been handled as outpatients because of mild disease, on average with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin; no patients required admission, developed ARDS, or died. Because of severe symptoms, 45/53 required admission: this cohort has been managed with immunosuppression withdrawal, methylprednisolone 16 mg/d, hydroxychloroquine, and antiviral drugs. Dexamethasone and tocilizumab were considered in case of ARDS. About 33% of the patients developed acute kidney injury, 60% ARDS, and 33% died. In this group, thrombocytopenia was associated to ARDS whereas lymphopenia at the baseline, higher D-dimer, and lack of C-reactive protein reduction were associated with risk of death. In the overall population, dyspnea was associated with the risk of ARDS and age older than 60 years and dyspnea were associated with the risk of death with only a trend toward an increased risk of death for patients on tacrolimus. In conclusion, SARS-CoV-2 infection may have a variable outcome in renal transplant patients, with higher risk of ARDS and death in the ones requiring admission.

Acute Kidney Injury due to Anticoagulant-Related Nephropathy : A Suggestion for Therapy.

The relationship between kidneys and anticoagulation is complex, especially after introduction of the direct oral anticoagulants (DOAC). It is recently growing evidence of an anticoagulant-related nephropathy (ARN), a form of acute kidney injury caused by excessive anticoagulation. The pathogenesis of kidney damage in this setting is multifactorial, and nowadays, there is no established treatment. We describe a case of ARN, admitted to our Nephrology Unit with a strong suspicion of ANCA-associated vasculitis due to gross haematuria and haemoptysis; the patient was being given dabigatran. Renal biopsy excluded ANCA-associated vasculitis and diagnosed a red blood cell cast nephropathy superimposed to an underlying IgA nephropathy. Several mechanisms are possibly responsible for kidney injury in ARN: tubular obstruction, cytotoxicity of heme-containing molecules and free iron, and activation of proinflammatory/profibrotic cytokines. Therefore, the patient was given a multilevel strategy of treatment. A combination of reversal of coagulopathy (i.e., withdrawal of dabigatran and infusion of its specific antidote) along with administration of fluids, sodium bicarbonate, steroids, and mannitol resulted in conservative management of AKI and fast recovery of renal function. This observation could suggest a prospective study aiming to find the best therapy of ARN.

Molecular and Biomechanical Clues From Cardiac Tissue Decellularized Extracellular Matrix Drive Stromal Cell Plasticity.

Decellularized-organ-derived extracellular matrix (dECM) has been used for many years in tissue engineering and regenerative medicine. The manufacturing of hydrogels from dECM allows to make use of the pro-regenerative properties of the ECM and, simultaneously, to shape the material in any necessary way. The objective of the present project was to investigate differences between cardiovascular tissues (left ventricle, mitral valve, and aorta) with respect to generating dECM hydrogels and their interaction with cells in 2D and 3D. The left ventricle, mitral valve, and aorta of porcine hearts were decellularized using a series of detergent treatments (SDS, Triton-X 100 and deoxycholate). Mass spectrometry-based proteomics yielded the ECM proteins composition of the dECM. The dECM was digested with pepsin and resuspended in PBS (pH 7.4). Upon warming to 37°C, the suspension turns into a gel. Hydrogel stiffness was determined for samples with a dECM concentration of 20 mg/mL. Adipose tissue-derived stromal cells (ASC) and a combination of ASC with human pulmonary microvascular endothelial cells (HPMVEC) were cultured, respectively, on and in hydrogels to analyze cellular plasticity in 2D and vascular network formation in 3D. Differentiation of ASC was induced with 10 ng/mL of TGF-ß1 and SM22α used as differentiation marker. 3D vascular network formation was evaluated with confocal microscopy after immunofluorescent staining of PECAM-1. In dECM, the most abundant protein was collagen VI for the left ventricle and mitral valve and elastin for the aorta. The stiffness of the hydrogel derived from the aorta (6,998 ± 895 Pa) was significantly higher than those derived from the left ventricle (3,384 ± 698 Pa) and the mitral valve (3,233 ± 323 Pa) (One-way ANOVA, p = 0.0008). Aorta-derived dECM hydrogel drove non-induced (without TGF-ß1) differentiation, while hydrogels derived from the left ventricle and mitral valve inhibited TGF-ß1-induced differentiation. All hydrogels supported vascular network formation within 7 days of culture, but ventricular dECM hydrogel demonstrated more robust vascular networks, with thicker and longer vascular structures. All the three main cardiovascular tissues, myocardium, valves, and large arteries, could be used to fabricate hydrogels from dECM, and these showed an origin-dependent influence on ASC differentiation and vascular network formation.

A report from the Brescia Renal COVID Task Force on the clinical characteristics and short-term outcome of hemodialysis patients with SARS-CoV-2 infection.

The SARS-CoV-2 epidemic is pressuring healthcare systems worldwide. Disease outcomes in certain subgroups of patients are still scarce, and data are needed. Therefore, we describe here the experience of four dialysis centers of the Brescia Renal COVID Task Force. During March 2020, within an overall population of 643 hemodialysis patients, SARS-CoV-2 RNA positivity was detected in 94 (15%). At disease diagnosis, 37 of the 94 (39%) patients (group 1) were managed on an outpatient basis, whereas the remaining 57 (61%) (group 2) required hospitalization. Choices regarding management strategy were made based on disease severity. In group 1, 41% received antivirals and 76% hydroxychloroquine. Eight percent died and 5% developed acute respiratory distress syndrome (ARDS). In group 2, 79% received antivirals and 77% hydroxychloroquine. Forty two percent died and 79% developed ARDS. Overall mortality rate for the entire cohort was 29%. History of ischemic cardiac disease, fever, older age (over age 70), and dyspnea at presentation were associated with the risk of developing ARDS, whereas fever, cough and a C-reactive protein higher than 50 mg/l at disease presentation were associated with the risk of death. Thus, in our population of hemodialysis patients with SARS-CoV-2 infection, we documented a wide range of disease severity. The risk of ARDS and death is significant for patients requiring hospital admission at disease diagnosis.

Mesenchymal stromal/stem cells as potential therapy in diabetic retinopathy.

Diabetic retinopathy (DR) is a multifactorial microvascular disease induced by hyperglycemia and subsequent metabolic abnormalities. The resulting cell stress causes a sequela of events that ultimately can lead to severe vision impairment and blindness. The early stages are characterized by activation of glia and loss of pericytes, endothelial cells (EC) and neuronal cells. The integrity of the retinal microvasculature becomes affected, and, as a possible late response, macular edema may develop as a common reason for vision loss in patients with non-proliferative DR. Moreover, the local ischemia can trigger vasoproliferation leading to vision-threating proliferative DR (PDR) in humans. Available treatment options include control of metabolic and hemodynamic factors. Timely intervention of advanced DR stages with laser photocoagulation, intraocular anti-vascular endothelial growth factor (VEGF) or glucocorticoid drugs can reduce vision loss. As the pathology involves cell loss of both the vascular and neuroglial compartments, cell replacement strategies by stem and progenitor cells have gained considerable interest in the past years. Compared to other disease entities, so far little is known about the efficacy and potential mode of action of cell therapy in treatment of DR. In preclinical models of DR different cell types have been applied ranging from embryonic or induced pluripotent stem cells, hematopoietic stem cells, and endothelial progenitor cells to mesenchymal stromal cells (MSC). The latter cell population can combine various modes of action (MoA), thus they are among the most intensely tested cell types in cell therapy. The aim of this review is to discuss the rationale for using MSC as potential cell therapy to treat DR. Accordingly, we will revise identified MoA of MSCs and speculate how these may support the repair of the damaged retina.

Endothelial Dysfunction in Early Systemic Lupus Erythematosus Patients and Controls Without Previous Cardiovascular Events.

OBJECTIVE: To assess the prevalence and risk factors for endothelial dysfunction detected by peripheral artery tonometry in systemic lupus erythematosus patients with early disease without cardiovascular disease and risk factors. METHODS: All the consecutive adult lupus patients, with a disease duration <5 years, seen in our hospital from December 2014 to March 2016 were considered. We excluded patients with any history of cardiovascular disease or risk factors possibly affecting peripheral artery tonometry. Enrolled patients were matched for sex, age, body mass index, and blood pressure with healthy controls with the same exclusion criteria. Patients and controls received a transthoracic Doppler echocardiogram and an evaluation of endothelial function by peripheral artery tonometry. RESULTS: Twenty patients (100% female) with a median disease duration of 14 months (range 1-58 months), a mean ± SD age of 42 ± 15 years, and a mean ± SD age at diagnosis of 40 ± 16 years were enrolled and matched with 20 controls. Peripheral artery tonometry showed a significantly higher prevalence of endothelial dysfunction (P = 0.003) and vascular stiffness (P = 0.02), while echocardiography detected a significantly higher prevalence of left ventricular concentric remodeling (P = 0.003), grade I diastolic dysfunction (P = 0.047), and subclinical increase of filling pressures (P = 0.039) in lupus patients compared to controls. Among lupus patients, no features were associated with endothelial dysfunction. CONCLUSION: A high rate of endothelial dysfunction and vascular stiffness occurs in early lupus patients without cardiovascular risk factors and disease. Larger studies are needed to confirm our results and to look for patients' characteristics possibly associated with these abnormalities.

The Pericytic Phenotype of Adipose Tissue-Derived Stromal Cells Is Promoted by NOTCH2.

Long-term diabetes leads to macrovascular and microvascular complication. In diabetic retinopathy (DR), persistent hyperglycemia causes permanent loss of retinal pericytes and aberrant proliferation of microvascular endothelial cells (ECs). Adipose tissue-derived stromal cells (ASCs) may serve to functionally replace retinal pericytes and normalize retinal microvasculature during disease progression. We hypothesized that Notch signaling in ASC underlies regulation and stabilization of dysfunctional retinal microvascular networks such as in DR. ASC prominently and constitutively expressed NOTCH2. Genetic knockdown of NOTCH2 in ASC (SH-NOTCH2) disturbed the formation of vascular networks of human umbilical cord vein endothelial cells both on monolayers of ASC and in organotypical three-dimensional cocultures with ASC. On ASC SH-NOTCH2, cell surface platelet-derived growth factor receptor beta was downregulated which disrupted their migration toward the chemoattractant platelet-derived growth factor beta subunits (PDGF-BB) as well as to conditioned media from EC and bovine retinal EC. This chemoattractant is secreted by pro-angiogenic EC in newly formed microvascular networks to attract pericytes. Intravitreal injected ASC SH-NOTCH2 in oxygen-induced retinopathy mouse eyes did not engraft in the preexisting retinal microvasculature. However, the in vivo pro-angiogenic capacity of ASC SH-NOTCH2 did not differ from controls. In this respect, multifocal electroretinography displayed similar b-wave amplitudes in the avascular zones when either wild type ASC or SH-NOTCH2 ASC were injected. In conclusion, our results indicate that NOTCH2 is essential to support in vitro vasculogenesis via juxtacrine interactions. In contrast, ongoing in vivo angiogenesis is influenced by paracrine signaling of ASC, irrespective of Notch signaling. Stem Cells 2018;36:240-251.

[Hyperuricemia and Gout]. / Iperuricemia e gotta.

Already known to ancient Egyptians, gout is one of the first diseases which have been described as a clinical entity. To date, gout is the most common form of inflammatory arthritis. Gout is defined by the deposition of monosodium urate crystals within tissues, causing episodes of acute arthritis and the development of tophi, nephrolithiasis, and urate nephropathy. Hyperuricemia, i.e. levels of serum uric acid above 6.8 mg / dL(404mol/L), is a condition necessary, yet not sufficient for gout to develop. The increasing incidence of risk factors such as hypertension, obesity, and renal failure together with an ever-growing life expectancy has led in recent decades to a significant increase in gout prevalence, which has more than doubled when compared to the 1960s. This article addresses the issue of gout by highlighting the role played by the kidneys in uric acid homeostasis; the clinical effect of crystal deposition in tissues, including the kidney; the more recent guidelines on diagnosis and management strategies, with special regard to the use of old and new drugs in renal patients.

[ADPKD: predictors of Renal Disease progression]. / ADPKD: fattori di progressione della Malattia Renale.

Factors predicting rapid progression of kidney disease in ADPKD can be divided into genetic (non-modifiable) and clinical (modifiable) risk factors. Patients harbouring PKD1 mutations, in particular if truncating, have a more severe form of ADPKD. Clinical risk factors include decrease in glomerular filtration rate and renal blood flow at a young age; high total kidney volume; hypertension and urological complications <35 years; albuminuria/proteinuria. The renal disease is also more severe in males and in subjects with family history of ESRD <55 years. In recent years, two models for predicting progression in ADPKD have been published: the Mayo model, based on height-adjusted TKV, age and eGFR, and the Brest model, based on PKD gene mutation type, gender, and early onset of hypertension and urological complications. With the emergence of new disease-modifying therapies, prediction tools are essential. However, the high variability in ADPKD makes the predicting models difficult to apply on an individual patient basis. Thus, the above-mentioned predicting models should be viewed as complimentary to clinical evaluation and follow-up. In the future, an individual risk score linking genetic, imaging and clinical data might prove the most accurate way of predicting long-term outcome.