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
NOTCH2 in adipose tissue‐derived stromal cells (ASCs) is essential for cell to cell communication. (a) Upon ASC NOTCH2 protein downregulation (ASC SH‐NOTCH2), PDGFRB expression was downregulated as well. ASC SH‐NOTCH2 were not able to migrate and acquire pericytic position in the mice retinal microvasculature. (b) Capillaries in the retina express a plethora of growth factors which are fundamental to attract cells of mesenchymal origin (ASC) to the site of injury. Platelet‐derived growth factor receptor beta on ASC promotes migration in response to endothelial secrete platelet‐derived growth factor beta subunits. ASCs can acquire pericytic position and exert their supportive function.
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 m
2
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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-β1 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-β1) differentiation, while hydrogels derived from the left ventricle and mitral valve inhibited TGF-β1-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.
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.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Introduction:
Cast nephropathy is a prevalent cause of acute kidney injury (AKI) in patients with myeloma.
Objectives:
The aim of this study is to define the outcome of a standardized supportive ...therapy for cast nephropathy.
Patients and Methods:
Retrospective analysis of the outcome of cast nephropathy in a University hospital for a period of five years. Data analysed; serum creatinine, estimated glomerular filtration rate (eGFR; mL/min/1.73 m
2
BSA) and need for dialysis. Standardized therapy with the aim of preventing/removing tubular casts; fluid administration and mannitol to increase urine flow, sodium bicarbonate to alkalize the urine and low dose steroid to reduce peritubular inflammation. Statistical analysis: Student’s t-test or the Mann-Whitney test according to data distribution. A two-tailed
P
value <0.05 was considered statistically significant. Survival curve was drawn according to Kaplan and Meier.
Results:
Twenty-seven cases were reviewed. Upon admission, mean serum creatinine was 7.1±4.9 mg/dL and mean eGFR 6±4 mL/min/1.73 m
2
BSA; 30% of patients had oligo-anuria. Diagnosis of cast nephropathy was presumptive in 23 patients, and renal biopsy proven in four. Hemodialysis was required by 10 (37%) patients, two of whom continued dialysis after discharge. At discharge, serum creatinine was 3.7±2.5 mg/dL and eGFR 20±13 mL/min/1.73 m
2
BSA (
P
=0.002), and after a median of 3.4 months, the values were 2.9±2.1 mg/dL and 35±32 mL/min/1.73 m
2
BSA, respectively. Patient survival was 60% after 24 months.
Conclusion:
Administration of fluid, mannitol, sodium bicarbonate and low-dose steroid may improve the outcome of cast nephropathy. Despite the fact that the study has many limitations, its findings could be the base for prospective controlled trials on cast nephropathy and could be useful in those countries where the expensive extracorporeal treatments are not available.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background and Aims
The start of peritoneal dialysis (PD) in patients affected by end stage renal disease (ESRD) may have a significant psychological impact. Aim of this study was to assess ...the most frequent reasons triggering the request of psychological referral in patients starting PD.
Method
A thematic analysis of the clinical diaries of the psychological support sessions of 15 consecutive patients requesting a psychological referral during the first 3 months of PD was performed from 2018 to 2021.
Results
Fifteen patients were enrolled, 6 women and 9 men. The median age was 59 (range 27–73) and the cause of the ESRD were glomerulonephritis (5/15), diabetic kidney disease (2/15), tubulo-interstitial (2/15), vascular nephropathy (1/15), other (5/15). The most frequent symptoms triggering the request for a psychological referral were insomnia and anxiety respectively in 12 and 15 cases. From the psychological assessments the most frequent causes of the patients’ symptoms have been identified as per follow: - Difficulties in elaborating and accepting the chronic disease (why me?) in 15 Patients.- Difficulties in accepting the esthetical impact of the peritoneal catheter (in the summer how will I do it?) in 15 patients.- The difficulties related to managing fluid restrictions in 15 patients- The limitations to traveling (what if something happens to me?) in 13 patients.- The difficulties to comply to the dietetic restriction (things taste like cardboard; I always eat the same things) in 7 patients.- Difficulties in accepting the dependency to the dialysis (I feel tied to the machine; you can’t do anything) in 6 patients.- The concerns related to the risks of developing peritonitis (fear of not doing the procedure correctly) in 5 patients.- The anxiety of not being able to fulfil the tasks requested by the treatment (I can’t; I lack air when I have to start dialysis) in 6 patients.
Conclusion
This qualitative study performed in PD patients during the first 3 months of dialysis identified the most frequent causes triggering the request of a psychological referral. These findings may be of help for the physicians in order to identify which aspects need to be better discuss during the pre-dialysis counselling and stresses the importance of the availability of a psychological support in a PD unit.
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.
Findings from an Italian cohort of kidney transplant patients with COVID‐19 support heterogenous disease courses with higher risks of acute respiratory distress syndrome and death in the subgroup with severe disease.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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