Kidney transplant recipients may be at a high risk of developing critical coronavirus disease 2019 (COVID‐19) illness due to chronic immunosuppression and comorbidities. We identified hospitalized ...adult kidney transplant recipients at 12 transplant centers in the United States, Italy, and Spain who tested positive for COVID‐19. Clinical presentation, laboratory values, immunosuppression, and treatment strategies were reviewed, and predictors of poor clinical outcomes were determined through multivariable analyses. Among 9845 kidney transplant recipients across centers, 144 were hospitalized due to COVID‐19 during the 9‐week study period. Of the 144 patients, 66% were male with a mean age of 60 (±12) years, and 40% were Hispanic and 25% were African American. Prevalent comorbidities included hypertension (95%), diabetes (52%), obesity (49%), and heart (28%) and lung (19%) disease. Therapeutic management included antimetabolite withdrawal (68%), calcineurin inhibitor withdrawal (23%), hydroxychloroquine (71%), antibiotics (74%), tocilizumab (13%), and antivirals (14%). During a median follow‐up period of 52 days (IQR: 16‐66 days), acute kidney injury occurred in 52% cases, with respiratory failure requiring intubation in 29%, and the mortality rate was 32%. The 46 patients who died were older, had lower lymphocyte counts and estimated glomerular filtration rate levels, and had higher serum lactate dehydrogenase, procalcitonin, and interleukin‐6 levels. In sum, hospitalized kidney transplant recipients with COVID‐19 have higher rates of acute kidney injury and mortality.
In this multinational cohort of 144 kidney transplanted patients from 11 transplant centers in the US and Europe who were hospitalized for COVID‐19, acute kidney injury occurred in 52% and respiratory failure requiring intubation occurred in 29%, with an overall mortality of 32%.
Mesenchymal stromal cells (MSCs) and renal stem/progenitors improve the recovery of acute kidney injury (AKI) mainly through the release of paracrine mediators including the extracellular vesicles ...(EVs). Several studies have reported the existence of a resident population of MSCs within the glomeruli (Gl-MSCs). However, their contribution towards kidney repair still remains to be elucidated. The aim of the present study was to evaluate whether Gl-MSCs and Gl-MSC-EVs promote the recovery of AKI induced by ischemia-reperfusion injury (IRI) in SCID mice. Moreover, the effects of Gl-MSCs and Gl-MSC-EVs were compared with those of CD133
progenitor cells isolated from human tubules of the renal cortical tissue (T-CD133
cells) and their EVs (T-CD133
-EVs).
IRI was performed in mice by clamping the left renal pedicle for 35 minutes together with a right nephrectomy. Immediately after reperfusion, the animals were divided in different groups to be treated with: Gl-MSCs, T-CD133
cells, Gl-MSC-EVs, T-CD133
-EVs or vehicle. To assess the role of vesicular RNA, EVs were either isolated by floating to avoid contamination of non-vesicles-associated RNA or treated with a high dose of RNase. Mice were sacrificed 48 hours after surgery.
Gl-MSCs, and Gl-MSC-EVs both ameliorate kidney function and reduce the ischemic damage post IRI by activating tubular epithelial cell proliferation. Furthermore, T-CD133
cells, but not their EVs, also significantly contributed to the renal recovery after IRI compared to the controls. Floating EVs were effective while RNase-inactivated EVs were ineffective. Analysis of the EV miRnome revealed that Gl-MSC-EVs selectively expressed a group of miRNAs, compared to EVs derived from fibroblasts, which were biologically ineffective in IRI.
In this study, we demonstrate that Gl-MSCs may contribute in the recovery of mice with AKI induced by IRI primarily through the release of EVs.
Extracellular vesicles (EVs) present in the urine are mainly released from cells of the nephron and can therefore provide information on kidney function. We here evaluated the presence of vesicles ...expressing the progenitor marker CD133 in the urine of normal subjects and of patients undergoing renal transplant. We found that EV expressing CD133 were present in the urine of normal subjects, but not of patients with end stage renal disease. The first day after transplant, urinary CD133+ EVs were present at low levels, to increase thereafter (at day 7). Urinary CD133(+) EVs significantly increased in patients with slow graft function in respect to those with early graft function. In patients with a severe pre-transplant vascular damage of the graft, CD133(+) EVs did not increase at day 7. At variance, the levels of EVs expressing the renal exosomal marker CD24 did not vary in the urine of patients with end stage renal disease or in transplanted patients in respect to controls. Sorted CD133(+) EVs were found to express glomerular and proximal tubular markers. These data indicate that urinary CD133(+) EVs are continuously released during the homeostatic turnover of the nephron and may provide information on its function or regenerative potential.
In renal transplanted patients, lymphoceles and lymphorrhea are well-known lymphatic complications. Surgical damage of the lymphatics of the graft during the procurement and of the lymphatic around ...the iliac vessels of the recipients has been associated with development of lymphatic complications. However, lymphatic complications may be related to medical factors such as diabetes, obesity, blood coagulation abnormalities, anticoagulation prophylaxis, high dose of diuretics, delay in graft function and immunosuppressive drugs. Consistently, immunosuppression regimens based on the use of mTOR inhibitors, especially in association with steroids and immediately after transplantation, has been associated with a high risk to develop lymphocele or lymphorrhea. In addition, several studies have demonstrated the association between rejection episodes and lymphatic complications. However, before the discovery of reliable markers of lymphatic vessels, the pathogenic mechanisms underlining the development of lymphatic complications during rejection and the influence of mTOR inhibitors remained not fully understood. The recent findings on the lymphatic systems of either native or transplanted kidneys together with the advances achieved on lymphangiogenesis shared some lights on the pathogenesis of lymphatic complications after renal transplantation. In this review, we describe the surgical and medical causes of lymphatic complications focusing on the rejection and immunosuppressive drugs as causes of lymphatic complications.
Extracellular vesicles (EVs) play an important role in cell-to-cell communication by delivering coding and non-coding RNA species and proteins to target cells. Recently, the therapeutic potential of ...EVs has been shown to extend to the field of solid organ transplantations. Mesenchymal stromal cell-derived EVs (MSC-EVs) in particular have been proposed as a new tool to improve graft survival, thanks to the modulation of tolerance toward the graft, and to their anti-fibrotic and pro-angiogenic effects. Moreover, MSC-EVs may reduce ischemia reperfusion injury, improving the recovery from acute damage. In addition, EVs currently considered helpful tools for preserving donor organs when administered before transplant in the context of hypothermic or normothermic perfusion machines. The addition of EVs to the perfusion solution, recently proposed for kidney, lung, and liver grafts, resulted in the amelioration of donor organ viability and functionality. EVs may therefore be of therapeutic interest in different aspects of the transplantation process for increasing the number of available organs and improving their long-term survival.
Serum is an abundant and accessible source of circulating extracellular vesicles (EVs). Serum-EV (sEV) pro-angiogenic capability and mechanisms are herein analyzed using an in vitro assay which ...predicts sEV angiogenic potential in vivo. Effective sEVs (e-sEVs) also improved vascular remodeling and prevented muscle damage in a mouse model of acute hind limb ischemia. e-sEV angiogenic proteomic and transcriptomic analyses show a positive correlation with matrix-metalloproteinase activation and extracellular matrix organization, cytokine and chemokine signaling pathways, Insulin-like Growth Factor and platelet pathways, and Vascular Endothelial Growth Factor signaling. A discrete gene signature, which highlights differences in e-sEV and ineffective-EV biological activity, was identified using gene ontology (GO) functional analysis. An enrichment of genes associated with the Transforming Growth Factor beta 1 (TGFβ1) signaling cascade is associated with e-sEV administration but not with ineffective-EVs. Chromatin immunoprecipitation analysis on the inhibitor of DNA binding I (ID1) promoter region, and the knock-down of small mother against decapentaplegic (SMAD)1-5 proteins confirmed GO functional analyses. This study demonstrates sEV pro-angiogenic activity, validates a simple, sEV pro-angiogenic assay which predicts their biological activity in vivo, and identifies the TGFβ1 cascade as a relevant mediator. We propose serum as a readily available source of EVs for therapeutic purposes.
Patients who underwent solid organ transplantation frequently suffer from different skin diseases, as consequence of the immunosuppressive treatment. Specific cutaneous side effects such as acne, ...hypertricosis or other pilosebaceous unit disorders, gingival hyperplasia, purpura or teleangiectasies are commonly associated to immunosuppressive medications. The majority of these conditions are benign, but the aesthetic concern may affect the patient is quality of life and reduce the adherence to the therapy. Moreover, solid organ transplant recipients frequently develop skin infections, as an indirect consequence of the immunosuppressive regimens. Herpes virus reactivation is more common few months after transplantation, whereas when the immunosuppression is reduced, the skin infections are mainly represented by human papilloma virus infections and localized mycosis. Bacterial infections are relatively rare. Long-term consequences of the immunosuppressive therapy are represented by development of precancerosis and skin cancers, with a risk that enhances over the time and a significant impact on patient survival. The aim of this paper is to provide an overview of the data published in the recent literature about this topic, in order to characterize the main skin disorders associated to the use of immunosuppressive drugs in solid organ recipients, giving information about their risk, epidemiology, clinical manifestations and management.
Background
Infection related to Coronavirus‐19 (CoV‐2) is pandemic affecting more than 4 million people in 187 countries worldwide. By May 10, 2020, it caused more than 280 000 deaths all over the ...world. Preliminary data reported a high prevalence of CoV‐2 infection and mortality due to severe acute respiratory syndrome related CoV‐2 (SARS‐CoV‐2) in kidney‐transplanted patients (KTRs). Nevertheless, the outcomes and the best treatments for SARS‐CoV‐2‐affected KTRs remain unclear.
Methods
In this report, we describe the clinical data, the treatments, and the outcomes of 5 KTRs with SARS‐CoV‐2 admitted to our hospital in Ancona, Marche region, Italy, from March 17 to present. Due to the severity of SARS‐CoV‐2, immunosuppression with calcineurin inhibitors, antimetabolites, and mTOR‐inhibitors were stopped at the admission. All KTRs were treated with low‐dose steroids. 4/5 KTRs were treated with hydroxychloroquine. All KTRs received tocilizumab up to one dose.
Results
Overall, the incidence of SARS‐CoV‐2 in KTRs in the Marche region was 0.85%. 3/5 were admitted in ICU and intubated. One developed AKI with the need of CRRT with Cytosorb. At present, two patients died, two patients were discharged, and one is still inpatient in ICU.
Conclusions
The critical evaluation of all cases suggests that the timing of the administration of tocilizumab, an interleukin‐6 receptor antagonist, could be associated with a better efficacy when administered in concomitance to the drop of the oxygen saturation. Thus, in SARS‐CoV‐2‐affected KTRs, a close biochemical and clinical monitoring should be set up to allow physicians to hit the virus in the right moment such as a sudden reduction of the oxygen saturation and/or a significant increase in the laboratory values such as D‐dimer.
Delayed graft function (DGF) is an early complication of kidney transplantation (KT) associated with increased risk of early loss of graft function. DGF increases using kidneys from extended criteria ...donors (ECD). NGAL is a 25KDa protein proposed as biomarker of acute kidney injury. The aim of this study was to investigate the role of NGAL as an early and accurate indicator of DGF and Tacrolimus (Tac) toxicity and as a mediator of tissue regeneration in KT from ECD.
We evaluated plasma levels of NGAL in 50 KT patients from ECD in the first 4 days after surgery or after Tac introduction.
Plasma levels of NGAL at day 1 were significantly higher in DGF group. In the non DGF group, NGAL discriminated between slow or immediate graft function and decreased more rapidly than serum creatinine. NGAL increased after Tac introduction, suggesting a role as marker of drug toxicity. In vitro, hypoxia and Tac induced NGAL release from tubular epithelial cells (TEC) favoring an autocrine loop that sustains proliferation and inhibits apoptosis (decrease of caspases and Bax/Bcl-2 ratio).
NGAL is an early and accurate biomarker of graft function in KT from ECD favoring TEC regeneration after ischemic and nephrotoxic injury.
Introduction
Megacalycosis is a rare disorder related to congenital underdevelopment of the renal papilla or structural defect of the renal calyces. Megacalycosis has a wide spectrum of clinical ...presentations ranging from simple variants without any significance on renal function to severe complications. Any prevention strategy is recommended yet since megacalycosis is mostly asymptomatic and usually discovered either accidentally or as result of its complications.
Case presentation
We observed megacalycosis progression in a young female with a single kidney toward progressive calyx dilatation for years, which ended in acute pyelonephritis. Conservative management, urinary drainage, and large‐spectrum antibiotics were unsuccessful and nephrectomy was required.
Conclusion
This rare case and literature review add evidence to identify prognostic factors to select patients with a high risk of complications (single kidney, bilateral disease, female gender, associated genetic syndromes, vesicoureteral reflux, and contralateral renal disorder). One o more factors should activate close monitoring and prophylactic therapy if needed.
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