Federica Urciuolo

Fatigue is still present in up to 40-50% of kidney transplant recipients (KTR), the results of studies comparing the prevalence among patients on hemodialysis (HD) and KTR led to conflicting results. Fatigue correlates include inflammation, symptoms of depression, sleep disorders and obesity. Fatigue in KTR leads to significant functional impairment, it is common among KTR poorly adherent to immunosuppressive therapy and is associated with a serious deterioration of quality of life. The following databases were searched for relevant studies up to November 2020: Medline, PubMed, Web of Science and the Cochrane Library. Several studies have compared the prevalence and severity of fatigue between KTR and hemodialysis or healthy patients. They have shown that fatigue determines a significant functional deterioration with less chance of having a paid job and a significant change in quality of life. The aim of the review is to report methods to assess fatigue and its prevalence in KTR patients, compared to HD subjects and define the effects of fatigue on health status and daily life. There is no evidence of studies on the treatment of this symptom in KTR. Efforts to identify and treat fatigue should be a priority to improve the quality of life of KTR.

Patients affected by chronic kidney disease (CKD) have an increased risk of developing cognitive impairment. The cause of mental health disorders in CKD and in chronic hemodialysis patients is multifactorial, due to the interaction of classical cardiovascular disease risk factors, kidney- and dialysis-related risk factors with depression, and multiple drugs overuse. A large number of compounds, defined as uremic toxins that normally are excreted by healthy kidneys, accumulate in the circulations, in the tissues, and in the organs of CKD patients. Among the candidate uremic toxins are several guanidino compounds, such as Guanidine. Uremic toxins may also accumulate in the brain and may have detrimental effects on cerebral resident cells (neurons, astrocytes, microglia) and microcirculation. The present study aims to analyze the effect of Guanidine on hippocampal excitatory postsynaptic field potentials (fEPSPs) and in CA1 pyramidal neurons recorded intracellularly. Moreover, we compared these effects with the alterations induced in vitro by CKD patients derived serum samples. Our results show an increased, dose-dependent, synaptic activity in the CA1 area in response to both synthetic Guanidine and patient's serum, through a mechanism involving glutamatergic transmission. In particular, the concomitant increase of both NMDA and AMPA component of the excitatory postsynaptic currents (EPSCs) suggests a presynaptic mechanism. Interestingly, in presence of the lower dose of guanidine, we measure a significant reduction of EPSCs, in fact the compound does not inhibit GABA receptors allowing their inhibitory effect of glutamate release. These findings suggest that cognitive symptoms induced by the increase of uremic compounds in the serum of CKD patients are caused, at least in part, by an increased glutamatergic transmission in the hippocampus.

Abstract BACKGROUND AND AIMS Haemolytic uremic syndrome (HUS) is a rare disease characterized by macroangiopathic haemolytic anaemia, thrombocytopaenia and severe AKI, belonging to the thrombotic microangiopathies (TMAs). It is divided into typical and atypical HUS: the first one occurs most frequently in children within the first 5 years of life and it is associated with Shiga-like toxin producing Escherichiacoli infection; the second one (aHUS) is less common (10%) and it is due to complement abnormalities with coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs or pregnancy. There is an increasing interest in SARS-CoV-2 infection as new trigger for complement activation. Nine cases of aHUS were recently associated with COVID-19, most of them occurring within 1 month from the infection. Available data suggest that SARS-CoV-2 is a potential trigger for aHUS: it can induce an over inflammatory state and to activate coagulation and complement pathway. Likewise, mRNA-based vaccines against COVID-19 inducing the expression of SARS-CoV-2 spike protein to stimulate immune recognition and antibody response could be a suitable trigger for HUS. METHOD We report the case of a 17-year-old woman, who presented at our emergency department with fever, dyspnoea, acute kidney injury AKI III with anuria, hypertension, severe anaemia, no diarrhoea, severe thrombocytopaenia and myocarditis, about 2 weeks after the first administration of SARS-CoV-2 vaccine (Comirnaty) and recent exposition to SARS-CoV-2 positive individual. SARS-CoV-2 nasal PCR swab was negative (as well as successive ones) and she was immediately admitted to paediatric intensive care unit and treated with transfusions and haemodialysis. Laboratory exams suggested a thrombotic microangiopathy with normal ADAMTS-13 activity and no E. coli infection. She underwent a renal biopsy that confirmed our hypothesis of aHUS: wrinkled capillaries, subendothelial expansion, mesangiolysis and rare thrombi in capillaries lumen. Arterioles had intimal proliferation with mucoid oedema who gave rise to onionskin like lesion that obliterates lumens. One glomerulus showed extracapillary proliferation (crescent), and there was interstitial lymphomonocytic inflammatory infiltration in the nearby. Also signs of acute tubular injury and atrophy were reported. Positive stain to fibrinogen in the arterioles at immunohistology was noted. She immediately performed genetic exams for aHUS-related complement mutations and she started immunosuppression with corticosteroids and eculizumab infusions. After 2 months of eculizumab, she was still oliguric, requiring renal replacement therapy. Genetic analysis showed no mutations. Therefore, she was examined for other genetic causes of thrombotic microangiopathies. RESULTS Finally, came to light that she had high levels of homocysteine, and she was diagnosed with secondary HUS associated with cobalamin C deficiency, which manifests with methylmalonic aciduria and homocystinuria due to a recessive mutation in the MMACHC gene, causing a cobalamin C type deficiency, which is the common functional variant of vitamin B12. After metabolic therapy with hydroxocobalamin, she gradually recovered diuresis and partially renal function without need for replacement therapy. CONCLUSION Reports from immunization programs show as myocarditis and thrombotic thrombocytopaenia are considered among main serious complications caused by COVID-19 vaccines, representing 12.6 cases per million doses and 0.73 cases per 100 000, respectively. This interesting case probably supports data about the role of mRNA-based anti-SARS-CoV-2 vaccines like a precipitant factor for TMAs. Moreover, our patient turned out to be an extremely rare case of HUS secondary to cobalamin C deficiency, that is generally diagnosed in early infancy and show typically neurological symptoms (absent in our case). Probably, the mRNA-based vaccine acted like ‘a second hit’, but existing predisposition should always be investigated including also the less frequent forms.

Background: Chronic kidney disease-associated pruritus (CKD-aP), defined as moderate to severe itching directly related to kidney disease, affects about one-third of haemodialysis patients and has been associated with poor quality of life, poor sleep, depression and increased mortality. Difelikefalin (DFK) is the first-in-class therapy approved by Food and Drug Administration and European Medicines Agency for this condition. The aim of the present study was to evaluate DFK efficacy and safety in a real-world setting in Italy. Methods: We retrospectively collected data for 20 patients treated with DFK in a compassionate manner, before the drug was commercialized, after obtaining approval by the relevant Ethics Committee for each individual case. Mean age and dialysis vintage were 72 ± 11 years and 54 ± 44 months, respectively; basal WI-NRS (24-h Worst Itching Intensity Numerical Rating Scale) score was 8.2 and 5D-ITCH was 18.6. Scratching lesions were detected in 15/20 patients. DFK was administered intravenously with weight-based dosing at the end of each dialysis session. Results: = 1). WI-NRS score improved >3 in 11/18 (61%) at Week 4 and in 16/18 (88%) at Week 12. 5D-ITCH decreased from basal 18.6 to 10.5 at Week 12, while sleep quality at the same time points changed from 2.6 to 5.8; scratching lesions disappeared in 12/15 (80%). Except for the two early therapy breaks, no other side effects were reported. Conclusions: In haemodialysis patients affected by CKD-aP, DFK is an effective and safe treatment that might clearly improve this distressing and overlooked condition.

Abstract Background and Aims Patients on chronic hemodialysis (HD) treatment had a higher mortality rate than the general population with SARS-CoV-2 infection. The ERA registry showed a 20% mortality at 28 days for these patients. The aim of the study was to evaluate the causes and risk factors of mortality for patients on chronic HD hospitalized with SARS-CoV-2 infection; particularly if the cause of death is directly attributable to the COVID-19 infection or to another pathology. Method Clinical data of chronic HD patients admitted for COVID-19 infection at Fondazione Policlinico Gemelli from March 15th 2020 to February 28th 2022 were analysed. Univariate and multivariate regression analysis for mortality risk factors was performed. Causes of mortality were obtained by hospital discharge forms. COVID-19 related cause of death was defined through intra-hospital codes as COVID-19 pneumonia, COVID-19 ARDS and COVID-19 respiratory failure. Results One hundred and fifty-two chronic HD patients were hospitalized for COVID-19 infection. Table 1 shows the general characteristics of the patients. The 28-day all-cause mortality was 21.9%, wich 11.9% was COVID-19 related. Table 2 shows the cause of mortality. Multivariate Cox regression demonstrated that an increased risk of death from COVID-19 at 28 days was significantly and independently associated with age >73 years (HR 1.05, 95% CI 1.0-1.09; p<0.05), Charlson Comorbidity Index (CCI) > 5 at entry (HR 1.28, 95% CI 1.02-1.60; p<0.01), Continuous Renal Replacement Therapies (CRRT) (HR 2.89, 95% CI 1.03-8.11; p = 0.04) and the presence of peripheral vasculopathy (HR 3.48, 95% CI 1.31-9.27; p = 0.01). Plasma albumin >25 g/L at entry (HR 0.87, 95% CI 0.80-0.96; p<0.01) and pre-admission SARS-CoV-2 vaccination (HR 0.25, 95% CI 0.09-0.72; p = 0.01) significantly reduced the risk of mortality. Conclusion Our study shows that on the total of deaths with a positive COVID-19 test, 59% were caused by the infection while the remaining 41% occurred from other causes. Age, CCI, the presence of peripheral vascular disease and the need for CRRT are independent risk factors for mortality. Vaccination was confirmed as a protective factor.