SARS-CoV-2 Infection and Pregnancy: Maternal and Neonatal Outcomes and Placental Pathology Correlations.

There is accumulating evidence on the perinatal aspects of COVID-19, but available data are still insufficient. The reports on perinatal aspects of COVID-19 have been published on a small group of patients. Vertical transmission has been noted. The SARS-CoV-2 genome can be detected in umbilical cord blood and at-term placenta, and the infants demonstrate elevated SARS-CoV-2-specific IgG and IgM antibody levels. In this work, the analysis of clinical characteristics of RT-PCR SARS-CoV-2-positive pregnant women and their infants, along with the placental pathology correlation results, including villous trophoblast immunoexpression status for SARS-CoV-2 antibody, is presented. RT-PCR SARS-CoV-2 amniotic fluid testing was performed. Neonatal surveillance of infection status comprised RT-PCR testing of a nasopharyngeal swab and the measuring of levels of anti-SARS-CoV-2 in blood serum. In the initial study group were 161 pregnant women with positive test results. From that group, women who delivered during the hospital stay were selected for further analysis. Clinical data, laboratory results, placental histomorphology results, and neonatal outcomes were compared in women with immunohistochemistry (IHC)-con SARS-CoV-2-positive and IHC SARS-CoV-2-negative placentas (26 cases). A positive placental immunoprofile was noted in 8% of cases (n = 2), whereas 92% of cases were negative (n = 24). Women with placental infection proven by IHC had significantly different pathological findings from those without. One infected neonate was noted (n = 1; 4%). Infection was confirmed in perinatal autopsy, as there was the intrauterine fetal demise. The potential course of the infection with the risk of vertical transmission and implications for fetal-neonatal condition is critical for proper clinical management, which will involve comprehensive, multidisciplinary perinatal care for SARS-CoV-2-positive patients.

Lung Congestion Severity in Kidney Transplant Recipients Is Not Affected by Arteriovenous Fistula Function.

Lung ultrasound is a bedside technique for the assessment of pulmonary congestion. The study aims to assess the severity of lung congestion in kidney transplant recipients (KTR) in relation to arteriovenous fistula (AVF) patency. One hundred fifty-seven patients at least 12 months after kidney transplantation were recruited to participate in a cross-sectional study. Apart from routine visits, lung ultrasound at 28 typical points was performed. The patients were assigned to either AVF+ or AVF- groups. The mean number of lung ultrasound B-lines (USBLs) was 5.14 ± 4.96 with no differences between groups: 5.5 ± 5.0 in AVF+ and 4.8 ± 4.9 in AVF-, p = 0.35. The number and proportion of patients with no congestion (0-5 USBLs), mild congestion (6-15 USBLs), and moderate congestion (16-30 USBLs) were as follows: 101 (64.7%), 49 (31.4%), and 6 (3.8%), respectively. In multivariate analysis, only symptoms (OR 5.90; CI 2.43,14.3; p = 0.0001), body mass index (BMI) (OR 1.09; CI 1.03,1.17; p = 0.0046), and serum cholesterol level (OR 0.994; CI 0.998,1.000; p = 0.0452) contributed significantly to the severity of lung congestion. Lung ultrasound is a valuable tool for the evaluation of KTR. Functioning AVF in KTR is not the major factor affecting the severity of pulmonary congestion.

The role of endothelin II type A receptor (ETAR) in transplant injury.

PURPOSE OF REVIEW: Antibody-mediated rejection is the leading cause of deterioration of graft function and graft loss after kidney transplantation. Recent studies have reported an increasing role of non-HLA antibodies in the humoral injury after kidney transplantation. We decided to present the influence of non-HLA antibodies - anti-endothelin II type A receptor (ETAR) on a transplanted kidney and characterize the significance of their receptor. RECENT FINDINGS: The role of non-HLA antibodies is still uncertain. Many studies suggest that the presence of non-HLA antibodies, including anti-ETAR antibodies, is among the risk factors for antibody-mediated rejection, graft injury, and graft loss. The discovery of new antigen targets and antibodies, which participate in the humoral response, has provided a significantly better understanding of the mechanism of antibody-mediated rejection after organ transplantation. SUMMARY: Endothelin and its receptors play an important role in physiology and pathophysiology after solid organ transplantation. ETAR and antibodies against ETAR may participate in humoral rejection and graft damage. The measurement of anti-ETAR antibodies may identify patients with an increased risk of rejection and even loss of a transplanted organ. Expression of ETAR detected in biopsy of transplant could become an additional tool used to better understand humoral activity. More research is needed to address many questions about non-HLA directed rejection and graft damage.

The Summarized Assessment of Endothelin A Receptor Expression in Renal Transplant Compartments Associated with Antibody-Mediated Rejection.

The occurrence of anti-endothelin A receptor antibodies may be useful in diagnosis of transplant damage. We noticed that the presence of the endothelin A receptor (ETA receptor) in biopsy compartments is yet to be defined. We decided therefore to analysed the presence and relevance of the ETA receptor in biopsy to define the cause. Our study aims to evaluate the expression of ETA receptors in renal recipients after a biopsy due to the worsening of transplant function. METHODS: The expression of ETA receptors was analyzed in renal transplant biopsies using the immunohistochemical method. The evaluation of ETA receptors was performed on paraffin sections. ETA receptor expression was analyzed in four compartments of renal transplant biopsies: glomeruli; vessels; tubular epithelium; and interstitium. The assessment was presented using a three-step scale (0: lack of expression; 1: mild to moderate immunoreactivity; 2: high expression). The results of each compartment from a single biopsy were summarized and assessed in the context of antibody-mediated rejection (AMR). RESULTS: We analyzed 156 patients who had a renal allograft biopsy after renal transplantation. For each patient, we created a summarized ETA receptor expression score. The summarized ETA receptor expression score analysis showed statistically significant differences in patients with and without AMR. In addition, we noticed that patients with AMR had a significantly higher mean summarized expression of ETA receptor score of 3.28 ± 1.56 compared to patients who had a biopsy for other reasons with a mean summarized ETA receptor expression score of 1.47 ± 1.35 (p < 0.000001). ROC analysis of the ETA receptor expression score for detecting AMR status showed that the most appropriate cut-off for the test of the chosen binary classifier is between 2 and 3 of the summarized ETA receptor expression score. CONCLUSIONS: The expression of endothelin A receptors in renal transplant compartments may be associated with antibody-mediated rejection. The positive ETA receptor staining might be a vital feature in the diagnosis of damage in AMR. The summarized ETA receptor expression score seems to be an exciting diagnostic tool in transplant injury assessment.

Comparing Humoral and Cellular Adaptive Immunity during Convalescent Phase of COVID-19 in Hemodialysis Patients and Kidney Transplant Recipients.

BACKGROUND: It is still unclear whether COVID-19 convalescent kidney transplant recipients (KTR) and hemodialysis (HD) patients can develop anti-SARS-CoV-2 adaptive immunity. The aim was to characterize and compare the immune response to the virus in HD patients and KTR. METHODS: The study included 26 HD patients and 54 KTR-both convalescent (14 HD, 25 KTR) and unexposed. The immune response was assessed by determining the anti-SARS-CoV-2 antibodies in serum and specific T cell response via the interferon-gamma release assay (IGRA). Moreover, blood-morphology-derived parameters, immune cell phenotypes, and acute phase reactants were evaluated. RESULTS: KRT and HD convalescents presented similar serum levels of anti-SARS-CoV-2 IgG and IgA. A negative correlation occurred between IgG and time after the infection was observed. There was a strong relationship between the prevalence of anti-SARS-CoV-2 cellular and humoral responses in both groups. Convalescent IGRA response was significantly higher in HD patients compared to KTR. CONCLUSIONS: HD patients and KTR develop humoral and cellular responses after COVID-19. The antibodies levels are similar in both groups of patients. SARS-CoV-2-reactive T cell response is stronger in HD patients compared to KTR. The SARS-CoV-2-specific IgG level decreases with time while IgA and a cellular response are maintained. IGRA proved to be a valuable test for the assessment of specific cellular immunity in immunocompromised HD patients and KTR.

Vascular Access Perspectives in Patients After Kidney Transplantation.

Introduction: More attention has been paid to the influence of arteriovenous fistula (AVF) on the cardiovascular system. In renal transplant recipients, some beneficial effect of an elective vascular access (VA) ligation was observed in patients with a high AVF flow. However, this strategy is not widely accepted and is in contradiction to the rule of vasculature preservation for possible future access. The aim of our study is to elucidate the vascular access function and VA perspective in the kidney transplantation (KTx) population. Materials and Methods: KTx patients with a stable graft function were recruited to participate in this single center observational study (NCT04478968). The measurement of VA flow and vessel mapping for future vascular access was performed by a color Doppler ultrasound. The study group included 99 (63%) males and 58 (37%) females; the median age was 57 (IQR 48-64) years. The median time from the transplantation to the baseline visit was 94 (IQR 61-149) months. Median serum creatinine concentration was 1.36 (IQR 1.13-1.67) mg/dl. Results: Functioning VA was found in 83 out of 157 (52.9%) patients. The sites were as follows: snuffbox in six (7.2%), wrist in 41 (49.4%), distal forearm in 18 (21.7%), middle or proximal forearm in eight (9.6%), upper-arm AV graft in one (1.2%), and upper-arm AVFs in nine (10.8%) patients, respectively. Blood flow ranged from 248 to 7,830 ml/min; the median was 1,134 ml/min. From the transplantation to the study visit, 66 (44.6%) patients experienced access loss. Spontaneous thrombosis was the most common, and it occurred in 60 (90.9%) patients. The surgical closure of VA was performed only in six (4%) patients of the study group with a functioning VA at the time of transplantation. Access loss occurred within the 1st year after KTx in 33 (50%) patients. Majority (50 out of 83, 60.2%) of the patients with an active VA had options to create a snuffbox or wrist AVF on the contralateral extremity. In a group of 74 patients without a functioning VA, the creation of a snuffbox or wrist AVF on the non-dominant and dominant extremity was possible in seven (9.2%) and 40 (52.6%) patients, respectively. In 10 (13.1%) patients, the possibilities were limited only to the upper-arm or proximal forearm VA on both sides. Access ligation was considered by 15 out of 83 (18.1%) patients with a patent VA. Conclusions: In the majority of the patients, vascular access blood flow was below the threshold of the negative cardiovascular effect of vascular access. Creation of a distal AVF is a protective measure to avoid a high flow and preserve the vessels for future access. The approach to VA should be individualized and adjusted to the patient's profile.

Exhausted Capacity of Bicarbonate Buffer in Renal Failure Diagnosed Using Point of Care Analyzer.

BACKGROUND: Metabolic acidosis in patients with chronic kidney disease (CKD) is a common complication. A bicarbonate concentration in venous blood (V-HCO3-) is a key index for diagnosis and treatment initiation. The aim of our study is to evaluate usability of acid-base balance parameters of in blood taken simultaneously from peripheral artery and the vein. METHODS: A total of 49 patients (median age 66 years [interquartile range IQR 45-75]), with CKD stage G4 or G5 were enrolled in this cross-sectional study. All patients were qualified for arteriovenous fistula creation in pre-dialysis period. The samples were taken during surgery, directly after dissection, and evaluated in a point of care testing analyzer. The arteriovenous difference in bicarbonate levels (Δ-HCO3-) was calculated. According to glomerular filtration rate (eGFR) the group was divided into Group A eGFR ≥ 10 mL/min/1.73 m2) and Group B eGFR < 10 mL/min/1.73 m2). RESULTS: In Group A Δ-HCO3- was significantly higher compared to Group B. No such differences were observed in the case of V-HCO3-. Δ-HCO3- positively correlated with eGFR. The discriminative power of Δ-HCO3- for predicting eGFR < 10 mL/min/1.73 m2 was 0.72 (95% confidence interval [CI] = 0.551-0.88; p = 0.01) which provided 67% sensitivity and 75% specificity. The best cut-off was 0.5 mmol/L. CONCLUSIONS: The Δ-HCO3- lower than 0.5 mmol/L may be used as predictor of exhaust buffer capacity. The value of this tool should be tested in larger population.

Knowledge, Attitudes and Practices of Flu Vaccination in Hemodialysis Patients.

BACKGROUND: Hemodialysis (HD) patients have an increased risk of morbidity and mortality due to infections. Despite the positive effect of vaccinations, the implementation of this method of prophylaxis is low. OBJECTIVES: This study aimed to explore the knowledge, attitudes and practices of flu vaccination among HD patients of two different dialysis centers. METHODS: A total of 193 patients (mean age 63.6 years), who voluntarily agreed to participate in an anonymous survey related to influenza vaccination, were enrolled in this cross-sectional study. RESULTS: A total of 45% of patients declared that they took regular, annual flu vaccination. In this group, 87.4% believed that vaccinations were effective. This opinion strongly correlated with the frequency of regular vaccinations (r = 0.56, p < 0.01). Multivariate logistic regression revealed that this opinion is an independent predictor of regular vaccinations with adjusted OR 9.86 (95% CI 4.36, 22.33). Groups of patients who had been irregularly or never vaccinated reject vaccinations for the following reasons: fear of adverse events-29.2%, conviction that vaccination was ineffective-26.4%, and lack of information about vaccination-22.6%. CONCLUSION: Knowledge among HD patients about the benefits of vaccinations is poor. Therefore, educational activities are required. Active vaccination promotion and education of patients rejecting this method of prevention play a key role in improving standards of care for HD patients.

Conversion From a Twice-Daily to a Once-Daily Tacrolimus Formulation in Kidney Transplant Recipients.

BACKGROUND: The aim of the study was to assess bioavailability aspects of tacrolimus formulations during conversion from twice-daily (TAC BID) to once-daily (TAC OD) formulation in 89 stable kidney transplant recipients. MATERIALS AND METHODS: The study included 89 stable kidney transplant recipients transplanted between 1998 and 2008 (37 female, 52 male, aged 46.0 ± 12.4 years) and followed for 10 years. For a comprehensive comparison of the different tacrolimus formulations, dose-normalized trough levels (ng/mL/mg total daily dose, C/D ratio) and their variability were studied for 10 consecutive visits before and 6 months after conversion. RESULTS: The mean trough level decreased significantly 14 days after conversion (16%, 5.77 ± 1.94 [5.6, 4.5-6.5] ng/mL, P < .001). There was no significant difference between the tacrolimus trough levels before and 3 months after conversion (6.92 ± 1.89 [6.8, 5.9-8.0] ng/mL, P = .548). The tacrolimus daily dose 3 months after conversion (4.56 ± 1.81 [4.5, 3.5-5.5] mg/d) was significantly higher than the dose before conversion (4.16 ± 1.80 [4.0, 3.0-5.0] mg/d, P = .006). The post-conversion mean TAC trough level (10 measures) (6.6 [6.2-7.0] ng/mL) was similar to preconversion level (6.8 [5.6-7.9] ng/mL, P = .203). C/D ratio as well as C/D intrapatient variability (CV%) did not change during conversion (C/D 1.68 [1.36-2.53] vs 1.74 [1.41 vs 2.31], P = .075; CV% 19.5 [16.4-26.6] vs 24.4 [17.5-28.3], P = .114). CONCLUSIONS: Conversion from TAC BID to TAC OD is associated with a significant increase in tacrolimus dose during the first 3 months. In a long-term observation both formulations present similar dose-normalized trough levels and variability.

Development and validation of limited sampling strategies for the estimation of mycophenolic acid area under the curve in adult kidney and liver transplant recipients receiving concomitant enteric-coated mycophenolate sodium and tacrolimus.

BACKGROUND: Mycophenolic acid (MPA) is widely used in solid organ transplantation. MPA absorption from enteric-coated mycophenolate sodium (EC-MPS) is delayed, which results in a delayed enterohepatic recirculation and subsequently higher and more variable MPA 12-hour trough concentration and tmax values. Therefore, MPA trough level monitoring cannot be used to monitor MPA exposure in patients who are given EC-MPS. The aim of the study was to develop and validate a limited sampling strategy (LSS) for accurate prediction of the 12-hour area under the concentration-time curve (AUC0-12h) for MPA in patients who receive concomitant EC-MPS and Tacrolimus (Prograf or Advagraf) within 196 months posttransplantation. According to our knowledge, the LSS for MPA AUC estimation using high-performance liquid chromatography to determine MPA concentrations in plasma samples of kidney and liver transplant patients receiving EC-MPS and Tacrolimus (Advagraf) has not been previously evaluated. METHODS: Seventy-four renal and liver transplant patients receiving EC-MPS and concomitant tacrolimus (either Prograf or Advagraf) provided a total of 74 pharmacokinetic profiles. MPA concentrations were measured using a validated high-performance liquid chromatography method for 9 plasma samples collected at predose and at 0.5, 1, 2, 3, 4, 6, 9, and 12 hours after the morning dose of EC-MPS after an overnight fast. LSS were developed and validated by stepwise multiple regression analysis with the use of a 2-group method (test, n = 37; and validation, n = 37). RESULTS: The 3 and 4 time point equations using C1h, C3h, C9h and C1h, C2h, C3h, C6h, respectively, were found to be superior to all other models tested. When these LSS models were tested in the validation group, the results were acceptable [for 3 time points equation: r = 0.824, percentage of prediction error: 6.32 ± 25.75, 95% confidence interval (CI): -40.71 to 79.76; percentage of absolute prediction error: 27.45 ± 29.89, 95% CI: 0.04-199.92, predictive performance, 71% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean ± SD: -0.03 ± 0.24; for 4 time points equation: r = 0.898, percentage of prediction error: 3.32 ± 18.26, 95% CI: -49.35 to 51.06; percentage of absolute prediction error: 14.05 ± 11.89, 95% CI 0.13-49.86, percentage of predictive performance, 83% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean ± SD: -0.01 ± 0.19]. CONCLUSIONS: LSS equations using concentrations at 1, 3, and 9 hours or 1, 2, 3, and 6 hours time points provided the most reliable and accurate estimations of the MPA AUC in stable renal and liver transplant recipients treated with EC-MPS and tacrolimus. Further studies on independent groups of patients are required to confirm clinical utility of the presented LSS models.

Increased aortic wall stiffness associated with low circulating fetuin A and high C-reactive protein in predialysis patients.

BACKGROUND/AIMS: Vascular calcification and arterial stiffening are cardiovascular risk factors among chronic kidney disease (CKD) patients. The aim of the study was to analyze relationships between inflammatory markers, fetuin A and arterial wall stiffness in CKD patients in the predialysis period and on maintenance dialysis. METHODS: Serum C-reactive protein (hs-CRP), fetuin A, interleukin 6 (IL-6) and other classical markers of atherosclerosis were measured in a group of 155 CKD patients (77 on hemodialysis, HD, 29 on peritoneal dialysis, 49 in CKD stage 5 in the predialysis period) and in 30 healthy volunteers. The aortic pulse wave velocity (aoPWV) was recorded using a tonometric method. RESULTS: The aoPWV, serum hs-CRP and IL-6 were higher and fetuin A levels were lower in all CKD groups than in controls. In multiple regression analysis, the age appeared as the strongest, independent factor increasing arterial wall stiffness in all investigated groups, including controls, whereas the association of aoPWV with IL-6 and fetuin A remained significant only in HD patients. CONCLUSIONS: Aortic wall stiffness is higher in CKD patients than in controls, and it already develops in the predialysis period. Age is the principal determinant of arterial wall stiffness also in CKD patients. The acceleration of arterial wall stiffness in CKD is associated with additional factors, i.e. fetuin A deficiency and higher CRP and IL-6.

IL-18 is involved in vascular injury in end-stage renal disease patients.

BACKGROUND: The role of interleukin (IL)-6 and IL-18 in induction of the inflammatory reaction underlying arteriosclerosis, and protective effect of an anti-inflammatory cytokine IL-10 in this process, have been confirmed by experimental and clinical observations. A systemic inflammatory reaction marker, C-reactive protein (CRP), is known to be associated with the induction of IL-6 and IL-18 release. The chronic inflammatory state associated with renal insufficiency contributes to acceleration of arteriosclerosis, reflected by decreased elasticity which can be measured with aortal pulse wave velocity (PWV). It is well known that chronic kidney disease (CKD) is associated with the chronic inflammatory process, as evidenced by increase in CRP and IL-6 level. It also results in a drop of fetuin-A concentration which is the calcification inhibitor negatively regulated by inflammation. Part of the derangements associated with the progressive renal failure is also the rise of activated monocyte pool, which among others produces IL-18. The aim of the present study was to evaluate, through measurements of CRP, fetuin-A and aortal pulse wave velocity (aoPWV), whether IL-6 and IL-18 affect the arterial wall of CKD patients as a part of general inflammatory process or locally, through their effect on the arterial lesion development. Materials and methods. The study was performed in a group of 102 patients with stage V CKD (73 treated with haemodialysis and 29 treated with continuous ambulatory peritoneal dialysis) (CKD5 group) and in 30 healthy controls. We measured serum high-sensitivity C-reactive protein (hs-CRP), fetuin-A, IL-6, IL-18, IL-10 (ELISA) and others (haemoglobin level, white blood cell count, serum calcium, phosphate, calcium-phosphate product, albumin, fibrinogen, cholesterol, high-density lipoprotein (HDL), triglycerides and parathormone). ECG-gated carotid and femoral artery waveforms were recorded and analysed. RESULTS: Serum levels of hs-CRP, IL-6, IL-10 and IL-18 were higher and fetuin-A levels were lower in the CKD5 group than in controls [6.4 (0.6-22.3) mg/dl versus 2.5 (0.5-5.2) mg/dl; 8.29 pg/ml (0.96-74.48)] versus 2.78 (7.91-0.77) pg/ml; 6.5 (3.7-29.7) pg/ml versus 4.1 (3.8-7.2) pg/ml; 254.4 (468.8-47.5) pg/ml versus 89.3 (91.3-27.5) pg/ml]. The aoPWV was higher in the CKD5 group patients than in the control group (9.4 +/- 1.75 m/s versus 7.76 +/- 1.67 m/s; P < 0.05, respectively). Serum fetuin-A level was negatively associated with hs-CRP and IL-6 but not with IL-18 or IL-10. The aoPWV positively correlated with hs-CRP (r = 0.246; P < 0.05), IL-6 and IL-18 (r = 0.220; P < 0.05) and negatively correlated with fetuin-A (r = -0.204; P < 0.05). No relationship between IL-10 and aoPWV was found. In a multiple regression analysis model respecting inflammatory markers the influence of hs-CRP, IL-18 and fetuin-A on aoPWV remained significant. CONCLUSIONS: The novel observations in the present study are the data indicating that the distinctive contribution of IL-18, but not IL-6, to the arteriosclerosis occurrence in CKD patients, is independent from CRP, fetuin A or other factors involved in the general inflammatory process.

[Mycophenolic acid concentration profiles may select recipients with high-risk of acute rejection in renal transplant recipients]. / Przydatnosc pomiarów stezenia kwasu mykofenolowego w osoczu w okresleniu zagrozenia wystapieniem ostrego odrzucania u biorców przeszczepu nerki.

UNLABELLED: The aim of the study was to assess relationship between the pharmacokinetics of mycophenolic acid (MPA) and the risk of developing acute rejection within 6 months after renal transplantation. MATERIAL AND METHODS: MPA concentrations were measured using validated HPLC. Venous blood samples for assay of MPA plasma concentrations were evaluated before (trough level; C) and 40 minutes, 1, 2 and 4 hours after mycophenolate mofetil (MMF) oral administration. The study included adult kidney cadaveric graft recipients: 26 patients treated with CsA, MMF and prednisone. MPA AUC was determined using the linear trapezoidal rule. Statistical significance was assessed using ANOVA Statistica. RESULTS: A total of 13 patients experienced biopsy proven rejection. Patients with acute rejection had lower GFR, lower serum albumin and were younger. There was statistically significant difference for MPA AUC(0-4), C40, C(max) between patients with acute rejection and patients with uneventful outcomes: mean MPA AUC(0-4): 11,4 +/- 7,23 microg x h/ml versus 34,0 26,8 microgxh/ml (p 0,01). Recipients with MPA AUC(0-4) <20 g x h/ml had a greater risk of acute rejection. CONCLUSIONS: MPA AUC(0-4) was a useful predictor of outcome in renal recipients within first 6 months after renal transplantation.