Successful Management of Severe COVID-19 in a Kidney Transplant Recipient Safe Co-Administered Tacrolimus and Ensitrelvir: A Case Report

Background and Aims Anemia is frequent in kidney transplant (KT) recipients, with multiple potential causes. Parvovirus B19 (PVB19) infection-associated pure red cell aplasia (PRCA) becomes an important diagnosis in KT recipients experiencing persistent anemia, in whom other etiologies have been excluded. PVB19-associated PRCA is described in up to 27% of KT recipients with anemia and recurrent disease in up to 33% of cases. The authors describe a case of a recurrent PVB19-associated PRCA in a KT recipient. Method - Results A 42-year-old male with chronic kidney disease of unknown etiology underwent KT from a deceased donor after circulatory death in January 2021. He received induction immunosuppression (IS) with thymoglobulin and maintenance IS with prednisolone, tacrolimus, and mycophenolate mofetil (MMF). Three months after KT, the patient complained of progressive asthenia, and normocytic normochromic (NN) anemia was detected. A thorough investigation revealed normal leucocyte and platelet counts, low reticulocyte count, and no signs of bacterial infection, iron deficiency, or hemolysis; thyroid function, erythropoietin, folate, and vitamin B12 levels were normal, direct Coombs test was negative and no monoclonal spike was detected on protein electrophoresis. Endoscopic studies and cervico-thoraco-abdomino-pelvic computer tomography were unremarkable. Serum PCR of PVB19 was positive and confirmed the diagnosis of PVB19-associated PRCA. MMF was discontinued but anemia continued aggravating (nadir hemoglobin [Hg] level of 6.6 g/dL) with a sustained PVB19 load. He was admitted to the hospital, received blood transfusions, and was started on intravenous immunoglobulin (IVIG) 2 g/kg. A bone marrow aspirate was performed and was compatible with recovery after erythroid aplasia. The patient was discharged with Hg 8 g/dL and reduced PVB19 load. Although MMF remained suspended, and close monitoring of Hg and PVB19 load was performed, four months later he developed recurrent PVB19-associated PRCA, which motivated another hospital admission for IVIG with excellent response. In addition, he presented kidney dysfunction, and a kidney biopsy revealed borderline acute T-cell mediated rejection. In this setting, IS was altered to TRANSFORM SCHEEME. Four months later, he presented a second recurrence of PVB19-associated PRCA, requiring new hospitalization and treatment with IVIG. Considering the recurrent PVB19-associated PRCA, in a patient with chronic allograft dysfunction, high immunologic risk, and the foscarnet's probable nephrotoxicity, preventive therapy with IVIG (0.4 mg/kg) every 4 weeks was started. After 7 months of preventive IVIG infusion, no relapse was identified, the Hg is 11.5 g/dL (and increasing, without erythropoiesis stimulants) and the PVB19 load remains low. Conclusion PVB19-associated PRCA is characterized by persistent NN anemia with low reticulocyte counts, which is unresponsive to erythropoietin. One significant risk factor is induction IS, particularly thymoglobulin. In the setting of solid organ transplants, the absence of PVB19 antibodies does not exclude this diagnosis and viral detection should be performed. The initial therapeutic approach involves reducing IS. However, the risk of allograft rejection must be acknowledged. If this approach proves insufficient, IVIG treatment is usually successful. In our patient, considering the facts that allograft rejection limits the reduction of IS, the need for blood transfusions, and the inherent immunization, in a young patient that will possibly require a second KT, the undesirable nephrotoxicity of foscarnet, the successful response to IVIG, and patient's quality of life, chronic IVIG therapy was thought to be the best choice and proved efficacious in preventing relapses. Despite the absence of precise guidelines for chronic PVB19 infection management, maintenance therapy with prolonged IVIG infusions may be a therapeutic option for recurrent PRCA, but more studies are necessary to define the appropriate duration of treatment.

Impact of Protease Inhibitor-Based Anti-Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients.

BackgroundIn acute respiratory distress syndrome (ARDS) patients, it has recently been proposed to set positive end-expiratory pressure (PEEP) by targeting end-expiratory transpulmonary pressure. This approach, which relies on the measurement of absolute esophageal pressure (Pes), has been used in supine position (SP) and has not been investigated in prone position (PP). Our purposes were to assess Pes-guided strategy to set PEEP in SP and in PP as compared with a PEEP/FIO2 table and to explore the early (1 h) and late (16 h) effects of PP on lung and chest wall mechanics.ResultsWe performed a prospective, physiologic study in two ICUs in university hospitals on ARDS patients with PaO2/FIO2 < 150 mmHg. End-expiratory Pes (Pes,ee) was measured in static (zero flow) condition. Patients received PEEP set according to a PEEP/FIO2 table then according to the Pes-guided strategy targeting a positive (3 ± 2 cmH2O) static end-expiratory transpulmonary pressure in SP. Then, patients were turned to PP and received same amount of PEEP from PEEP/FIO2 table then Pes-guided strategy. Respiratory mechanics, oxygenation and end-expiratory lung volume (EELV) were measured after 1 h of each PEEP in each position. For the rest of the 16-h PP session, patients were randomly allocated to either PEEP strategy with measurements done at the end. Thirty-eight ARDS patients (27 male), mean ± SD age 63 ± 13 years, were included. There were 33 primary ARDS and 26 moderate ARDS. PaO2/FIO2 ratio was 120 ± 23 mmHg. At same PEEP/FIO2 table-related PEEP, Pes,ee averaged 9 ± 4 cmH2O in both SP and PP (P = 0.88). With PEEP/FIO2 table and Pes-guided strategy, PEEP was 10 ± 2 versus 12 ± 4 cmH2O in SP and 10 ± 2 versus 12 ± 5 cmH2O in PP (PEEP strategy effect P = 0.05, position effect P = 0.96, interaction P = 0.96). With the Pes-guided strategy, chest wall elastance increased regardless of position. Lung elastance and transpulmonary driving pressure decreased in PP, with no effect of PEEP strategy. Both PP and Pes-guided strategy improved oxygenation without interaction. EELV did not change with PEEP strategy. At the end of PP session, respiratory mechanics did not vary but EELV and PaO2/FIO2 increased while PaCO2 decreased.ConclusionsThere was no impact of PP on Pes measurements. PP had an immediate improvement effect on lung mechanics and a late lung recruitment effect independent of PEEP strategy.

Aims: Evaluate cardiovascular impact related to the use of non steroidal anti-inflammatory drugs in a Health Area, by estimating the connection between the previous medical prescription of non steroidal anti-inflammatory medicines and acute coronary syndrome.Material and Methods: A retrospective observational study of clinical casecrosover during 5 years is done, from 1st of January 2008 to 31st of December 2012. In first place patients were cases and controls (n=1.317) who suffered cardiovascular accidents and went to Emergency Room. Setting: Alcazar de San Juan Health Care Area. Main measurements: Association of the risk of acute coronary syndrome by Odds Ratio with consumption of non anti-inflammatory drug.Results: The connection between acute coronary syndrome and the use of anti-inflammatory drugs was positive and significant (OR 1.42; IC95% 1.06-1.9), which means the probability of suffering a cardiovascular accident increases to 42% in patients taking non steroidal anti-inflammatory drugs. The connection between the prescription of anti-inflammatory drugs and acute coronary syndrome reached a bigger magnitude in patients with less comorbidity, Charlson ≤ 1 (OR 1.66; IC95% 1.15 – 2.40) as opposite to those with more comorbidity, Charlson > 1 (OR 1.07; IC95% 0.65 – 1.76). This change of effect was due, in part, to the concomitant use of medicines which prevent cardiovascular diseases, such as antiaggregant, anticoagulant and statins drugs.Conclusions: The use of non steroidal anti-inflammatory drugs has been connected to a higher risk of cardiovascular accidents; therefore it is necessary to realize follow-up patients who consume these drugs. These drugs must not be consumed for a long time or at high doses.

BackgroundCMV infection is common post-kidney transplant (KT). Valganciclovir (VGC) prophylaxis (Px) has lessened CMV infection among high-risk (CMV D+/R-) KT recipients (KTRs), but VGC can induce neutropenia. We quantified the burden of CMV infection among CMV D+/R- KTRs and healthcare resources required to manage these patients (pts).MethodsRetrospective study of pts undergoing KT between Jan 2014-Dec 2018. Study and control groups (gps) were CMV D+/R- and R+ KTRs, respectively. Standard post-KT immunosuppression was tacrolimus and mycophenolate mofetil (MMF). D+/R- and R+ KTRs received VGC Px (900 mg/day) for 6 and 3 months (mos), respectively.ResultsClinical characteristics did not differ between D+/R- (n=131) and R+ (n=140) pts. Median VGC Px duration was longer for D+/R- (183 vs 104 days, p< .01). Within the first 6 mos post KT, a higher proportion of D+/R- KTRs received ≥1-course of granulocyte-stimulating factor (G-CSF) (15% vs 6%, p=.02). VGC Px was stopped prematurely/intermittently in 20% and 10% of D+/R- and R+, respectively, due to neutropenia (p=0.02); corresponding data for stopping MMF for ≥1 mos were 32% and 21% (p=.05). 50% of D+/R- pts received < 3 mos Px. Leukopenia prompted hospitalization in 3% of D+/R- vs 0% of R+ pts (p=.05). CMV infections did not differ between gps (7% vs 6%, p=.80); however, VGC-resistant CMV was higher in D+/R- gp (3% vs 0%, p=.05). Between 6-12 mos post-KT, D+/R- KTRs had higher rates of CMV infection (24% vs 4%,p< .01), VGC resistance (5% vs 0%, p=.01), hospitalization due to CMV (11% vs 2%, p=.01), MD intervention (22% vs 2%,p< .01), and infectious disease (ID) referral (8% vs 2%,p= .04). 57% of CMV resistance was observed in pts who prematurely stopped VGC. Hospitalizations were longer for CMV infections in D+/R- KTRs (8 vs 1 d, p< .01). There was a trend toward higher rejection for D+/R- KTRs (13% vs 6%, p=.09).ConclusionUniversal VGC Px in D+/R- KTR remains challenging and requires significant resources for monitoring and intervention for neutropenia, including MD involvement and ID referral. Intermittent/premature stop of VGC may have led to VGC-resistant CMV,and stop of MMF may have led to a trend of higher cellular rejection at 1 yr. There is critical need for new CMV agents with a better safety profile.DisclosuresAmit D. Raval, PhD, Merck and Co., Inc. (Employee) Yuexin Tang, PhD, JnJ (Other Financial or Material Support, Spouse’s employment)Merck & Co., Inc. (Employee, Shareholder) Cornelius J. Clancy, MD, Merck (Grant/Research Support) Minh-Hong Nguyen, MD, Merck (Grant/Research Support)

Morris CR, Harvey IM, Stebbings WSL, Speakman CTM, Kennedy HJ, Hart AR (School of Medicine, Health Policy and Practice, University of East Anglica, Norwich, United Kingdom). Do calcium channel blockers and antimuscarinics protect against perforated colonic diverticular disease? A case control study. Gut 2003;52:1734–1737.

COVID-19 in Kidney Transplantation: Outcomes, Immunosuppression Management, and Operational Challenges.

Low immunization rates among kidney transplant recipients who received 2 doses of the mRNA-1273 SARS-CoV-2 vaccine

Prone and Lateral Positioning in Spontaneously Breathing Patients With COVID-19 Pneumonia Undergoing Noninvasive Helmet CPAP Treatment

Evidence of potent humoral immune activity in COVID-19-infected kidney transplant recipients.

Steroid Withdrawal: Moving on to the Next Questions

Association of Antisecretory Drugs with Upper Gastrointestinal Bleeding in Patients Using Oral Anticoagulants: A Systematic Review and Meta-Analysis

BACKGROUNDHumoral response after two doses of mRNA-based SARS-CoV-2 vaccines is weak in kidney transplant recipients (KTRs) [1]. Of concern, even a third dose of the mRNA-1273 vaccine induced a suboptimal humoral response in a cohort of KTRs who did not respond after two doses [2]. However, the assessment also of the T-cell immune response of mRNA vaccines in KTRs is limited in the literature [3]. Herein, we report the evaluation of humoral response induced after a third dose of the mRNA-1273 vaccine in a cohort of KTRs and T-cell immune responses in not responders to the third dose.METHODSObservational cohort data were collected from KTRs actively followed up in our outpatient clinic, with no history of COVID-19 infection, who received a third mRNA-1273 vaccine dose, 6 months after the second dose, as per suggested local policy.The primary endpoint was the humoral response provided at least 4 weeks after the third dose compared with the humoral response after the second dose.Anti-S1-RBD IgG antibodies were determined using a fluoroimmunoenzymatic method (Thermo Fisher Scientific), and the quantitative result expressed in BAU/mL (reference interval: <28 Negative; 28–40 Borderline; >40 Positive; linear range between 0.7 and >1632 according to the manufacturer). In seronegative and borderline KTRs after the third dose, an INFγ-release assay (IGRA) [Euroimmun, Lubeck, Germany] was used to detect T-cell immune responses. A patient result was considered negative, borderline and positive when IFNγ values were respectively <100, 100–200 and >200 mIU/mL.RESULTSSixty KTRs received a third dose of the mRNA-1273 vaccine. Overall, we obtained the antibody titre in 57 KTRs at a median of 23 days (IQR: 22–31) after the second dose and 23 days (IQR: 21–26) after the third dose.After the second dose, positive antibody titres were detectable in 28 KTRs (49%), and 2 KTRs (4%) had a borderline positivity. While after third dose, positive and borderline antibody responses were observed in 40 (70%) and 4 (7%) KTRs, respectively.Among all 57 KTRs, the median anti-S1-RBD IgG titre significantly increased after the third dose ( 448 versus 39 BAU/mL; P = 0.0018; Mann–Whitney test). While in 28 KTRs already seropositive after the second dose, the median antibody titre increased from 556 to >1632 BAU/mL (P = 0.0285; Mann–Whitney test). Figure 1 shows the kinetics of anti-S1-RBD IgG titres after the second and the third dose for all the 57 KTRs.Among 17 KTRs with negative and borderline humoral responses after the third dose, IFNγ values were positive and borderline in only 1 (6%) and 1 (6%) KTRs, respectively. The median IFNγ value was 22 mIU/mL (IQR: 0–1014).The 34 KTRs receiving mycophenolate mofetil (MMF) were less likely to develop adequate immune responses than the 23 KTRs not receiving MMF; 12 KTRs (35%) receiving MMF had no antibody and IFNγ positive response after the third dose in comparison to 4 KTRs (17%) not receiving MMF, and the median anti-S1-RBD IgG titre beyond the two groups after the third dose was statistically different (205 versus > 1632; P = 0.0046; Mann–Whitney test).CONCLUSIONSIn this study, the third dose of the mRNA-1273 vaccine increases the rate of positive antibody responses in non-responders KTRs after the second dose, and improves the magnitude of these responses in already seropositive KTRs. However, a fraction of KTRs still lacks protective antibody titres and T-cell responses after a third dose, with mycophenolate mofetil to be associated with poor immune responses. Alternative vaccination protocols are needed to protect this high-risk group.

Patients treated with hemodialysis are often immunocompromised due to concomitant disease. As a result, this population is at high risk of infection and mortality from COVID-19. In addition to symptomatic treatment, a series of antiviral drugs targeting COVID-19 are now emerging. However, these antivirals are used mainly in mild or moderate patients with high-risk factors for progression to severe disease and are not available as pre- or post-exposure prophylaxis for COVID-19. There is a lack of clinical data on the use of anti-COVID-19 drugs, especially in patients treated with hemodialysis, therefore, vaccination remains the main measure to prevent SARS-CoV-2 infection in these patients. Here, we review the clinical features and prognosis of patients on hemodialysis infected with SARS-CoV-2, the main anti-COVID-19 drugs currently available for clinical use, and the safety and efficacy of anti-COVID-19 drugs or COVID-19 vaccination in patients treated with hemodialysis. This information will provide a reference for the treatment and vaccination of COVID-19 in patients treated with hemodialysis and maximize the health benefits of these patients during the outbreak.

The pharmacokinetics of mycophenolic acid (MPA) and its glucuronide (mycophenolic acid phenolic glucuronide, MPAG) in lupus nephritis (LN) have not been fully characterized. The aim of this study was to evaluate the pharmacokinetics of MPA and MPAG in LN patients by comparing the pharmacokinetics with those of kidney transplant (KT) recipients. Six LN patients (World Health Organization class IV and V) and 24 KT recipients [8 recipients treated with tacrolimus (Tac) and 16 with cyclosporine (CyA)] during the early posttransplantation period were enrolled. Pharmacokinetic parameters of MPA and MPAG were compared between LN patients and Tac-treated or CyA-treated KT recipients. The area under the concentration-time curve (AUC0-12) of MPA normalized to mycophenolate mofetil (MMF) dose (mg/kg) was significantly lower in LN patients and CyA-treated KT recipients than in Tac-treated KT recipients [median (range), 2.19 (0.87-4.23), 2.36 (1.13-5.74), and 4.86 (3.25-6.75) microg x h/mL per mg/kg, P < 0.05 and P < 0.01, respectively]. Dose-normalized MPAG AUC0-12 was significantly lower in LN patients and slightly lower in Tac-treated KT recipients than in CyA-treated KT recipients [median (range), 35.0 (8.34-69.8), 51.6 (34.4-94.8), and 84.1 (34.7-152) microg x h/mL per mg/kg, P < 0.05 and P = 0.13, respectively]. The ratio of MPA AUC5-12 to AUC0-12, an estimate of MPA enterohepatic recirculation, was slightly higher in LN patients and Tac-treated KT recipients than in CyA-treated KT recipients [median (range), 0.44 (0.35-0.56), 0.45 (0.42-0.61), and 0.34 (0.22-0.55), P = 0.29 and P = 0.10, respectively]. Serum creatinine was significantly lower in LN patients than in Tac-treated and CyA-treated KT recipients. In conclusion, the pharmacokinetics of MPA in LN patients is characterized by high MPA clearance and in CyA-treated KT recipients. Despite this higher clearance of MPA, MPAG AUC0-12 was lower in LN patients most likely due to better renal function in LN patients.