key: cord-1034160-0w0pjjg1
authors: Abu Jawdeh, Bassam G.
title: COVID-19 in Kidney Transplantation: Outcomes, Immunosuppression Management and Operational Challenges
date: 2020-07-17
journal: Adv Chronic Kidney Dis
DOI: 10.1053/j.ackd.2020.07.004
sha: 921dbde9c45c65ea3027067c5a655ce2dd1b85f4
doc_id: 1034160
cord_uid: 0w0pjjg1

Abstract The Coronavirus disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2, has led to the death of hundreds of thousands of people worldwide. If infected, older individuals and those with diabetes, hypertension, cardiovascular disease and compromised immune systems are at higher risk for unfavorable outcomes. These comorbidities are prevalent in patients with kidney disease, hence the significant burden of COVID-19 on kidney transplant programs. Multiple case series of kidney transplant recipients with COVID-19 have shown increased mortality compared to non-transplant patients. To-date, we do not have high-level evidence to inform immunosuppression minimization strategies in infected transplant recipients. Most centers however have adopted early anti-metabolite withdrawal in addition to other interventions. This review summarizes the published COVID-19 literature as it relates to outcomes and immunosuppression management in kidney transplant recipients. It also discusses challenges pertaining to pre-transplant evaluation and wait-listed patients.

The Coronavirus disease 2019 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2, has led to the death of hundreds of thousands of people worldwide. If infected, older individuals and those with diabetes, hypertension, cardiovascular disease and compromised immune systems are at higher risk for unfavorable outcomes. These multiple studies have elucidated that COVID-19 is a systemic disease that often manifests with gastrointestinal (GI) symptoms, liver injury, cardiac involvement, encephalitis, atypical stroke, acute kidney injury (AKI) in addition to endothelial cell injury and coagulopathy -the likely mediators of multi-organ involvement (3) (4) (5) (6) (7) (8) .

Six retrospective studies from New York and Europe have reported on COVID-19 in KTR (Table   1 ) (9) (10) (11) (12) (13) (14) . In a 36-patient study, the median age was 60 years, 72% were male, 39% were African American and 75% received deceased-donor kidney transplants (DDKT)(9).

Comorbidities included diabetes (69 %), hypertension (94%), smoking (36%) and cardiovascular disease (17%). Forty-two percent received lymphocyte depleting induction and more than 85%

were on mycophenolate / tacrolimus / prednisone maintenance immunosuppression. Upon presentation, less than a half had no fever, about a fifth presented with GI symptoms and a third with myalgias. All but one of 28 hospitalized patients had radiologic evidence of a viral pneumonia. Out of those, eleven patients required mechanical ventilation and six developed AKI warranting renal replacement therapy (RRT). Ten patients died at a median of 21 days, among them two who were being monitored at home. Both were recent transplant recipients who received anti-thymocyte globulin within 5 weeks of presentation.

In a study of 15 hospitalized KTR at Columbia University, the median age was 51 years, 65% were male and 80% received DDKT(10). Maintenance immunosuppression consisted mostly of an anti-metabolite / tacrolimus / prednisone regimen. Notably, the Columbia transplant program adopts an early steroid withdrawal strategy, however their sample was enriched with patients on prednisone maintenance (67%) which confirms the plausible role of enhanced immunosuppression as a susceptibility factor. It is also worth mentioning that two of their patients were maintained on a belatacept-based regimen. Upon presentation, about 90% of KTR had fever, two-thirds, one-third and one-fifth had cough, dyspnea and GI symptoms respectively, whereas a third had no radiologic finding of a pneumonia. Four and two patients required mechanical ventilation and RRT respectively. Among those who were intubated, two were in their first-year post transplant. One developed symptoms and deteriorated while on plasmapheresis and glucocorticoids treatment for antibody-mediated rejection. The other developed symptoms just after completing anti-thymocyte globulin induction. One patient had DGF in setting of COVID-19 infection and two died. Nair et al. reported a case series of 10 KTR with COVID-19, median age of 57 years, 60% male and 40% DDKT recipients (11) . Ninety percent of those patients required hospitalization, 50% developed AKI and 30% required mechanical ventilation and eventually died.

A paper from Northern Italy reported on 20 patients with a median age of 59 years and 13 years since transplant (12) . They were 80% male, 15% diabetic, 85% hypertensive, 15% had cardiovascular disease and the majority were on a mycophenolate / calcineurin-inhibitor (CnI) / prednisone regimen. All patients presented with fever, half with cough and about 15% with GI symptoms. Almost half of the patients required ventilation, a third developed AKI with one patient requiring RRT. Mortality was 25% at median follow up of 15 days from onset of symptoms. In a 33-patient report from Spain, mortality was comparable to the general population at 6%, however several patients where still hospitalized when the study was completed (13) .

The largest published experience to-date comes from New York (14) . It included 90 solid organ transplant recipients out of which 46 were KTR. Median age was 57 years, 59% were male, 46% were diabetic, 64% hypertensive and 63% had baseline chronic kidney disease. Atypical GI and constitutional symptoms were common upon presentation. Immunosuppression modification included antimetabolite withdrawal in 88% and CnI cessation or reduction in 18% of the cohort. Hydroxychloroquine and azithromycin were used in the majority, whereas tocilizumab and glucocorticoids were used in about a fifth of the cases. Patients with more severe disease tended to be older and overall mortality was 18%. Also, important to note is that 8% initially tested negative for COVID-19 before repeat testing --based on high clinical suspicion --turned positive.

Retrospective, unpublished data from the University of Washington on more than 300 solid organ transplant patients with COVID-19, more than two-thirds of which are KTR, shows that the demographics of these patients are consistent with the published reports: median age of 57 years and 35% African American. Interestingly, nearly half of these patients had no fevers, 15% had absent respiratory symptoms, 25% had normal chest imaging and more than 50% were lymphopenic upon presentation. Upward of 70% were hospitalized early in their course, 30% treated in the Intensive care Unit and 22% required intubation. Most of them were also treated with some off-label or experimental therapy.

In summary, COVID-19 could present in an atypical fashion in KTR, with no fever, respiratory symptoms or radiologic findings of pneumonia. This raises the question of the validity of using these symptoms and signs to rule out SARS-CoV-2 infection with good enough sensitivity. We should be also cognizant of GI symptoms which could be confounded or augmented by immunosuppressive medications, mainly mycophenolate (4, 5) . Majority of patients were male which is consistent with earlier studies from China, and in their sixth decade of life. This is slightly older than the general COVID-19 population and likely represents the relatively increased age of KTR (2, 15, 16). The AKI incidence was elevated. This reflects diminished kidney reserve in KTR secondary to solitary kidney, CnI use and suboptimal baseline allograft function (17) . The mortality rate was between 13 and 30%, which is higher than that of the general population (~5%). This could be attributed to the increased prevalence of diabetes, hypertension and cardiovascular disease in addition to the immunosuppressed state -all of which have been associated with severe COVID-19. Moreover, these studies are retrospective and focus on cohorts of patients that mostly required hospitalization. This prevents us from assessing the true incidence of infection in KTR and could have possibly skewed the AKI and mortality rates.

It remains unclear how to best manage immunosuppression in transplant recipients with COVID-19. Liang et al. have shown that cancer patients with neutropenia have unfavorable outcomes (18) . This underscores the role of the immune system in fighting SARS-CoV-2. It is then plausible that there is room for immunosuppression reduction to help alleviate the progression of SARS-CoV-2 infection. The flip-side however, maybe losing the potential beneficial effect of immunosuppressive drugs in mitigating the systemic inflammatory response mediated by cytokine storm (19) . Actually, in addition to anti-virals, many of the treatment strategies currently being investigated for COVID-19 are examining adjunctive medications that primarily target the inflammatory response (20) . Some of these therapies such as glucocorticoids, interleukin-6 (IL-6) receptor antagonists, anti-complement-5 inhibitors, intravenous immunoglobulins and mammalian target of rapamycin (m-TOR) inhibitors have been used for primary prevention and treatment of allograft rejection (21) (22) (23) (24) .

By using human cDNA libraries, genome-wide coronavirus yeast-two-hybrid experiments demonstrated that cyclophilin and FK-binding protein interacted with SARS-CoV-1 nonstructural protein 1 (25) . Subsequent experiments showed in-vitro efficacy of cyclosporine A and FK506 in inhibiting the replication of SARS-CoV-1 and other human coronaviruses (25) . This data might offer a justification for leaving patients on a lower dose CnI while de-escalating other medications. A reasonable first step is to reduce or hold the anti-metabolite. Indeed, up to 100% of the patients in the above-reported experiences have had mycophenolate withdrawn.

Furthermore, in a national survey by Boyarsky et al. responders discontinued anti-metabolites and reduced CnI in 92% and 27% of KTR respectively (26) . In the case series from Italy and Spain, all maintenance immunosuppression was held upon presentation and substituted by methylprednisolone or prednisone (12, 13) . Another consideration is the potential interaction between antivirals such as lopinavir/ritonavir and other investigational medications with immunosuppressives, mainly calcineurin and m-TOR inhibitors (27) . Immunosuppression dose adjustment and more frequent trough monitoring would be prudent in this case.

The increased mortality seen in KTR with COVID-19 corroborates the role of diminished T-and B-cell immunity as a predisposing factor for severe infection. To-date though, we do not have a level 1 evidence-based strategy to inform immunosuppression management. In those with moderate disease, it would be reasonable to hold the anti-metabolite and continue low dose CnI with or without glucocorticoids. In patients with severe disease and those who are critically ill, it may be justifiable to hold all maintenance immunosuppression and initiate remdesivir in addition to stress-dose steroids (28). Other investigational drugs should be offered under IRB-approved prospective, controlled, research protocols.

Inflammatory biomarkers such as C-reactive protein, IL-6 levels and ferritin have correlated with the severity of disease, nevertheless with substantial overlap and variability among subjects (29). Trending biomarkers in individual patients however might play a role in guiding an individualized immunosuppression adjustment plan. An example would be using tocilizumab, a monoclonal antibody against the IL-6 receptor, in patients with significantly elevated IL-6 levels.

The COVID-19 pandemic has taken its toll on kidney transplant programs and resulted in suspending or restricting their operations. This led to unfavorable consequences that have impacted wait-listed patients and complicated the care of KTR. Discussed below, are some of the concerns and challenges that relate to kidney transplantation practices.

The consensus is that kidneys from deceased or living donors with a confirmed infection or high exposure risk to COVID-19 should not be used(30).

To-date, donor to recipient viral transmission lacks conclusive confirming data, however it is certainly plausible. This is supported by the following: i) Angiotensin converting enzyme 2 (ACE2) is the receptor that binds the spike protein of SARS-CoV-2 and facilitates its entry into target cells (31) . Among all organs, the kidney shows the highest level of expression of ACE2 (32) . ii) Indeed, SARS-CoV-2 can directly infect the kidneys. Ultrastructural tissue analysis by electron microscopy demonstrated viral particles in tubular epithelial and glomerular capillary endothelial cells (33, 34) . This could contribute to the AKI seen in patients with COVID-19, however this discussion is beyond the scope of this manuscript. iii) SARS-CoV-2 viremia and viruria have been reported in 15% and 7% of COVID-19 patients respectively (15, 35) . This might even be an underestimation as data from the 2003 SARS outbreak show an RNAemia rate of 78% in the earlier weeks of the illness (36) . All this will become obsolete if an efficacious anti-viral drug is discovered. Then, we would be dealing with a situation similar to that of hepatitis C after the discovery of direct-acting antivirals (37) .

Sixteen percent of all COVID-19 patients are healthcare-workers and 29% of those had hospital-acquired infections (38, 39) . Data from the 2003 SARS and MERS outbreaks suggest that immunosuppressed patients could have more prolonged shedding while staying asymptomatic (40) . Therefore, organ procurement team members as well as transplant physicians following KTR could act as vectors for nosocomial spread, which underscores the importance of appropriate physical distancing, hygiene, handwashing and personal protective equipment for all team members.

There has been significant heterogeneity among different kidney program practices; however, the majority restricted their operations. In a survey of U.S. centers by Boyarsky et al., 72% and 24% of living donor transplant programs reported complete or partial suspension of activities respectively.

Only 20% of deceased donor programs continued with no restrictions (26) . It is reasonable to defer DDKT for non-sensitized patients on the top of the list, as they will likely get more offers in the near future. We do not have this luxury however with the extremely sensitized who might not get another opportunity soon enough. Therefore, an individualized approach to wait-listed patients would be inescapable (Figure 1 ).

The majority of programs have adopted universal donor and recipient screening by nasopharyngeal (NP) nucleic acid testing (NAT) before transplantation. Only 17% had blood NAT available to rule out viremia (26) . A study from Spain during the peak of the pandemic, reported a moratorium on recipients and donors who had COVID-19 or a high exposure risk.

However, they did consider infected donors 21 days after resolution of symptoms and only after viral clearance was confirmed (38) . In another Chinese experience, all potential donors where screened with NP NAT in addition to chest CT. During their hospitalization, KTR received standard immunosuppression and wore surgical masks. If a KTR was suspected with COVID-19, he would be isolated and only return to the regular transplant floor after CT chest and NAT NP came back negative (41) .

For post-transplant care of KTR, 98% of centers have limited in-person clinic visits and 97% reported incorporating tele-medicine instead (26) .

Suspending kidney transplantation will prolong waiting times, so are we trading-off COVID-19-related mortality with mortality on the waiting list? (38, 42) . It is still early to make this determination. Moreover, except for end-stage kidney disease patients running out of dialysis access options, kidney transplantation remains a semi-elective procedure when we consider short-term outcomes. Amidst the magnitude of this pandemic, and itshopefully -time-limited nature, it is reasonable to restrict and then gradually reinstate transplant activities based on the future COVID-19 trajectory. How this is executed will vary based on the geographic location of each transplant center.

Several unanswered questions remain. When is it safe to accept kidneys from COVID-19 individuals who have recovered? (43) Is there a role for serologic testing? Does the presence of antibodies confer complete protection against re-infection? What is the optimal immunosuppression management strategy? What can we learn from allograft biopsies about the susceptibility of kidney tissue for direct infection by SARS-CoV-2? And finally, will COVID-19 be around until we have evidence-based answers to all these questions?

The COVID-19 pandemic has impacted transplantation and is associated with increased mortality in infected KTR. Without the availability of high-level evidence, most kidney programs developed internal protocols to deal with new transplants and manage immunosuppression in KTR. Until effective therapies and a vaccine become available, we have to deal with this "new normal" while taking care of our susceptible patient population. It is imperative for transplant providers to have a low threshold for suspecting SARS-CoV-2 infection, and promptly initiating appropriate evaluation and immunosuppression reduction (Figure 1 ). -Hold anti-metabolite and reduce CnI trough target to 3-5 ng/ml ± low dose glucocorticoids until patient improves. 

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