key: cord-0741469-7numfkp4 authors: Alfano, G.; Damiano, F.; Fontana, F.; Ferri, C.; Giaroni, F.; Melluso, A.; Montani, M.; Morisi, N.; Plessi, J.; Tei, L.; Giovanella, S.; Ligabue, G.; Mori, G.; Guaraldi, G.; Magistroni, R.; Cappelli, G. title: Effects of immunosuppressive therapy reduction and early post-infection graft function in kidney transplant recipients with COVID-19 date: 2021-06-07 journal: nan DOI: 10.1101/2021.06.06.21258414 sha: 62f795105ea955b5e773f2b2ebf33b7973cd7fe6 doc_id: 741469 cord_uid: 7numfkp4 Kidney transplant (KT) recipients with COVID-19 are at high risk of poor outcomes because of comorbidities and long-term immunosuppressive therapy (IST). There are little data on the effect of IST reduction and early graft function after COVID-19. We conducted a retrospective study on 45 consecutive KT recipients followed at the University Hospital of Modena who tested positive for COVID-19 by RT-PCR analysis. We detailed clinical management and outcomes of these patients. Median age of patients was 56.1 (interquartile range, [IQR] 47.3-61.1) years with a predominance of male (64.4%) and patients of Caucasian origin (91.1%). Kidney transplantation vintage was 10.1 (2.7-16) years, and more than half (55.6%) was on triple IST. Therapeutic management included antimetabolite (62.8%) and calcineurin inhibitor withdrawal (22.2%), and suspension of IST in severely ill patients. Of the 45 patients, 88.9% became symptomatic and 40% required hospitalization. Overall mortality accounted for 17.8% (n=8). There were no differences in outcomes between full- and reduced-dose IST at the end of follow-up. Overall, early graft function after COVID-19 showed a stable and unmodified kidney function in 95% of survivors. Risk factors for death were age (odds ratio [OR]: 1.19; 95% CI: 1.01-1.39), and years spent on immunosuppression (OR: 1.96; 95% CI: 0.38-10.03-4.9). One patient experienced symptomatic reinfection with COVID-19 after primary infection and anti-SARS-CoV-2 mRNA vaccine. COVID-19 impacted the graft and general survival of KT recipients. Short-term graft outcome after COVID-19 was favorable in most survivors. Age and transplantation vintage are independent predictors of death in our patients. Since SARS CoV-2 was identified in December 2019, the pandemic spreads quickly all around the world with a disruptively impact on social and economic life. This virus yielded several new challenges to our healthcare systems that had to copes with an increase of morbidity and mortality among the most vulnerable populations. [1] Kidney transplant (KT) recipients is a subset of the population at high risk of severe COVID-19 relate consequences due to comorbidities, consequences of chronic kidney disease (CKD) and the burden of immunosuppressive therapy (IST), which in some subjects include also therapies administered before kidney transplantation to treat glomerulonephritis or underlying autoimmune diseases. [2] Data collected so far reported that transplant recipients were at higher risk of morbidity and mortality compared to the general population [3, 4] . Despite the great emphasis on IST reduction to face the potentially lethal consequences of COVID-19, no confirming data supports its beneficial effect in terms of survival or clinical and laboratory manifestations. Additional uncertainty arises from recent literature when the tempered immune response is suggested to prevent COVID- 19- induced systemic inflammatory syndrome leading acute respiratory distress syndrome and sepsis. Furthermore, few data are available regarding early graft outcomes after COVID-19 in survivors. [5] . Multiple causes, including kidney tropism of SARS-CoV-2 [6] may be responsible for non-reversible episodes of AKI[7] that can severely impair graft survival. Lastly, a concerning issue is the hyporesponsiveness to anti-SARS-CoV-2 vaccination [8] . Numerous studies have confirmed that KT recipients have a blunted immune response to mRNA vaccine [9] . Only 48% of patients was able to mount a protective serologic response to SARS-CoV-2[10]. Caillard et al [11] reported that about one-third of kidney transplant patients had severe manifestations, including a fatal outcome, after completing vaccination with mRNA. This group of patients is therefore expected to remain vulnerable to the severe complications of COVID-19 until new strategies will be implemented to reduce the susceptibility of these subjects. Considering all the uncertainties in the management of KT recipients and the still current risk of infection in this cohort of patients we report our experience in managing KT recipients with All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.21258414 doi: medRxiv preprint COVID-19. In particular, we will focus on the impact of early IST reduction and early graft function after the resolution of the infection. This kidney transplant outpatient clinic follows more than 500 KT recipients, including combined liver and pancreas-kidney transplantation. Outpatient service was delivered by a senior nephrologist with experience in kidney transplantation, one fellow and three nurses. A 24-h, 7/7 days per week service was available for KT recipients in case of kidney-related pathologic process (anuria, fluid overload) or infections. This service was also offered to the subjects transplanted in our Center but living far from it. During COVID-19 all the patients were instructed to call the clinic in case of COVID-19 symptoms. Despite the reduction of non-essential healthcare services, our outpatient clinic continued to deliver care for KT recipients adopting all the containment measures (triage at entry, masking, social distance and cleaning hands) to prevent COVID-19 diffusion. A telephonic triage was performed for all patients before reaching the hospital to intercept some paucisymptomatic patients. Patients with symptoms were invited to perform RT-PCR on nasal swab and were visited in a dedicated room to assessed vital parameters and clinical conditions. According to the severity of symptoms, patients were sent home or to the emergency room. To reduce the workload to the emergency room, patients were managed as an outpatient unless they developed severe symptoms requiring hospital admission. Remote patient monitoring was performed principally with phone calls and email. According to our internal protocol and taking into account European expert opinions [12, 13] , immunosuppressive was modulated as follow: -for asymptomatic or mild COVID-19 (e.g., mild upper respiratory and/or gastrointestinal symptoms, temperature < 38°C without dyspnea) in patients on triple therapy (calcineurininhibitors [CNI] + mycophenolate acid [MPA]/ azathioprine [AZA] + steroids), MPA or AZA was All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.21258414 doi: medRxiv preprint withdrawn, and a dual therapy (CNI + steroid) was continued. If patient the patient was on dual therapy (CNI+ mammalian target of rapamycin inhibitor [MPA/mTOR-i]), MPA/mTOR was withdrawal and replaced with a low dose of steroids. -for moderate and severe COVID-19 all immunosuppressors but steroid were stopped The study population was comprised of kidney transplant recipients with COVID-19 followed in the nephrology outpatient clinic at the University Hospital of Modena. This outpatients clinic delivers care to all patients after three months from kidney transplantation. We retrospectively reviewed the electronic charts of all KT recipients with COVID-19 from March 7, 2019, to June 25, 2021. The diagnosis of COVID-19 was performed through reverse transcriptase-polymerase chain reaction (RT-PCR) assay on a nasal swab. We excluded patients aged<18 years. Kidney function was estimated by glomerular fraction rate (eGFR) using CKD-EPI equation. Missing occurred for patients admitted to a hospital located far from our Center. This study has been authorized by the local Ethical Committee of Emilia Romagna (n. 839/2020). The study protocol complies with the guidelines for human studies and includes evidence that the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Baseline characteristics were described using median (interquartile range [IQR]), mean and standard deviation (SD), or frequencies, as appropriate. The chi-square or Fisher's test, and student's t-test were used to compare categorical and continuous variables between groups, respectively. Univariate and multivariate logistic regression were performed to test the association between mortality and baseline patient characteristics. Variables that were significant on univariate analysis (P =<0.1) were entered into the multivariate model to identify independent predictors (P= < 0.05). Results were expressed as odds ratios (OR) and 95% confidence intervals (CI). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.21258414 doi: medRxiv preprint Univariate and multivariate logistic regression analysis determined risk factors for death. A P value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS® statistical software. From the spread of COVID-in Italy, 45 KT recipients followed in at our Center contracted COVID- 19 . The demographic and clinical characteristics of the patients were detailed in Table 1 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.21258414 doi: medRxiv preprint Among survivors, one patient with a CKD stage 4 (GFR=20 ml/min) before SARS-CoV-2 infection, developed irreversible graft failure requiring HD. In one patient presenting with de-novo proteinuria (4100 mg/die) after resolution of COVID-19, graft biopsy revealed IgA glomerulonephritis (available data to do allow to classify these histological findings as de-novo or recurrent IgA [15, 16] . We found that in a cohort of 45 KT recipients of 56.1 years with COVID-19, 40% of them developed severe symptoms requiring hospitalization. Overall mortality was 17.8%, higher than the national mortality reported in the general population, which ranges between 0.1-9.2% among countries worldwide and account for about 2% globally[17]. Since IST portends poor outcomes in patients with infections, a new therapeutic strategy was set to reduce the burden of IST in COVID-patients. In the attempt to reconstitute the immune system against SAR-CoV-2 infection, we systematically minimized anti-rejection therapy. All KT recipients, who communicated their COVID-19 positivity, were advised to withdraw at least antimetabolite agents (MFA or AZA). In hospitalized patients, IST was reduced or suspended according to the clinical All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.21258414 doi: medRxiv preprint conditions of the patient. Nevertheless, hospitalization and death rate in the reduced-dose IST group was not dissimilar from full-dose IST group. A potential explanation for this result is that reduction of immunosuppressive therapy was not able to reconstitute an efficient immune response after the long-term burden of IST. Although IST reduction did not lead to a favorable outcome, it is worth mentioning that the overall mortality estimated in our cohort was tendentially lower than that reported in several monocentric and multicentric studies where this approaching up to 32.5% [18] [19] [20] [21] [22] [23] [24] [25] . Our results are in line with the population-based data on 1013 KT recipients affected by COVID-19 collected by French and Spain national registries, which reported a 28-day mortality of 20% [26] . In Brescia (Italy), Bossini et al. [23] reported a higher overall mortality rate among KT recipients (28%) during the first wave of the infection. Similar to our therapeutic strategy, they practiced immunosuppression cessation in all hospitalized patients and introduced or increased the glucocorticoid dose. At first glance, the causes of this different mortality rate are unknown. The different timing of enrollment made the two cohorts not perfectly comparable. The enrollment of all patients of the Brescia cohort during the first wave has probably magnified the risk of side effects of therapeutic regimens administered during the first wave [27, 28] and the challenges to delivering the standard of care in an overwhelmed and unprepared hospital. Lastly, a lower age (56.1 vs 60 years) in our cohort of patients has probably contributed to lead to a better prognosis. Multivariate analysis showed that the predictors of death were age and time elapsed on IST, in line with previous studies. Age is widely associate with COVID-19 severity and death in KT recipients [29, 30] as well as the general population [31] . Centers for Disease Control (CDC) claims that 8 out 10 COVID-19 death in the U.S. has been reported in adults aged more 65 years and the risk of hospitalization and death increases enormously with age. [32] The effect of immunosuppression is still controversial in KT recipients [33] . Immunosuppression is known to dysregulate innate and adaptive immunity, exposing the patients to severe infections. On All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.21258414 doi: medRxiv preprint the other hand, severe COVID-19 infection has been associated with a dysregulated inflammatory response (IL-6, IL-1, and chemokines) leading to ARDS and sepsis. The new insights support a promising role of immunosuppressants in the most severe case on COVID-19(i.e., tocilizumab, steroid) [34] . In our opinion, the interplay between immunosuppression and pathogenesis of COVID-19 should be contextualized with the stage of SARS-CoV-2 infection. The high rate of symptomatic disease is probably secondary to the host susceptibility due to immunodepression and the burden of CKD. If the IST is somewhat beneficial to reduce the pro-inflammatory release of cytokines in the second phase of infection, more studies are required to elucidate which molecular pathway is involved. Lastly, we report a short-term good graft function in survival after COVID-19. These data indicate a stable early graft function (sCr and 24-hour proteinuria) in outpatients COVID-19 who were not hospitalized. Conversely, hospitalized KT recipients had a statistically significant improvement in renal function. As supported by Dacina et al [5] we speculate that lower sCr after the COVID-19 episode was due to the minimization or withdrawn of CNI, a 'drug holiday' without apparently dire consequences in terms of graft rejection for 95% of survivors. Some limitations of the study should be enunciated. It is a retrospective study, with small sample size and a short follow-up after COVID-19. The small number of patients in full-and reduced-dose of IST group may have reduced the probability to observe an underlying difference between these two groups. Furthermore, we cannot exclude that in some cases, reduction of the IST occurred after a short delay from the diagnosis of COVID-19. However, all patients with symptoms or at risk of contagious underwent nasal swab as fast as possible in an ambulatory setting. Reduction of immunosuppression did not reduce the risk of severe COVID-19 or death. Age and time spend on kidney transplantation are independent predictors of death in our patients. Short-term All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 7, 2021. follow-up after COVID-19 showed an excellent graft function in most survivors. Primary infection or vaccination do not exclude the risk of SARS-CoV-2infection in KT recipients. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.21258414 doi: medRxiv preprint eGFR denotes estimated glomerular filtration rate; HCV, hepatitis C; HBV, hepatitis B; IST, immunosuppressive therapy; MPA, mycophenolate acid; mTOR-I, mammalian target of rapamycin inhibitor; sCr, serum creatinine. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.21258414 doi: medRxiv preprint Occurrence of severe COVID-19 in vaccinated transplant patients Expert-opinion-on-ISD-in-Covid-19.pdf [Internet La pandemia del nuovo coronavirus 2019 ed il trapianto renale Routine use of immunosuppressants is associated with mortality in hospitalised patients with COVID-19 Evaluation, and Treatment of Coronavirus (COVID-19). 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