Effects of COVID19 Pandemic on Pediatric Kidney Transplant in the United States

In March 2020, COVID-19 infections began to rise exponentially in the United States, placing substantial burden on the healthcare system. As a result, there was a rapid change in transplant practices and policies, with cessation of most procedures. Our goal was to understand changes to pediatric kidney transplantation (KT) at the national level during the COVID-19 epidemic. Using SRTR data, we examined changes in pediatric waitlist registration, waitlist removal or inactivation, and deceased donor and living donor (DDKT/LDKT) events during the start of the disease transmission in the United States compared to the same time the previous year. We saw an initial decrease in DDKT and LDKT by 47% and 82% compared to expected events and then a continual increase, with numbers reaching expected pre-pandemic levels by May 2020. In the early phase of the pandemic, waitlist inactivation and removals due to death or deteriorating condition rose above expected values by 152% and 189%, respectively. There was a statistically significant decrease in new waitlist additions (IRR 0.49 0.65 0.85) and LDKT (IRR 0.17 0.38 0.84) in states with high vs low COVID activity. Transplant recipients during the pandemic were more likely to have received a DDKT, but had similar cPRA, waitlist time and cause of ESRD as before the pandemic. The COVID-19 pandemic initially reduced access to kidney transplantation among pediatric patients in the United States, but has not had a sustained effect.


Introduction
As the death toll from COVID-19 in the United States surpasses 180,000 fatalities, the pandemic continues to place considerable burden on the health care system. Many transplant centers have been challenged to determine how to proceed with organ transplantation during a time of limited data and resources. These decisions have had profound implications for many patients awaiting transplantation, including the pediatric population, where kidney transplantation (KT) remains the optimal treatment for end-stage renal disease (ESRD) [1].
Adult KT has been signi cantly impacted by COVID-19, with reduced new wait-list addition and transplantation at many transplant centers across the nation [2,3]. A national survey of adult transplant centers showed that 72% had suspended live donor kidney transplants (LDKT) and 84% had placed signi cant restrictions on deceased donor kidney transplants (DDKT) by April 2020 [4]. The stringency of these restrictions varied by center, with more restrictive measures in areas with a higher incidence of COVID-19. Several reasons have been cited for these changes. First, there is concern that organ transplant recipients may be at a greater risk for acquiring and experiencing worse clinical outcomes to COVID-19 infection [5][6][7]. Second, immunosuppressed KT recipients may have prolonged viral shedding and transmissibility, potentially posing a greater risk to public health [8,9]. Third, there is concern that hospitals will not have the resources to safely perform KT and provide the necessary post-operative care [10]. These changes are not without consequences; postponing KT can lead to a higher waitlist mortality, and diverting resources away from transplant recipients may worsen post-operative outcomes [11,12].
It is unclear if the pandemic has resulted in similar challenges and restrictions for the pediatric population. For the most part, children are asymptomatic or have milder infection and fewer complications from COVID-19 compared to adult patients [13,14]. From the limited data available, it appears that disease severity even among immunocompromised children remains less severe than that of the general adult population and remains similar to healthy children [15][16][17]. Furthermore, while pediatric patients in general have less dialysis-associated morbidity and mortality compared to adults, delaying transplantation and prolonging time on dialysis is associated with increased morbidity and repetitive risk of COVID exposure during in-center dialysis sessions [18,19]. The response of the pediatric transplant community is likely different than adult practices and therefore needs to be studied separately.
To investigate center-speci c changes in pediatric transplant practices during the COVID-19 pandemic, we used national registry data to quantify changes to KT waitlist registration, waitlist deaths or removal, rates of DDKT and LDKT, between February and June 2020. We examined rates of these waitlist events among the overall patient population, and evaluated for differences in patient characteristics during the COVID-19 pandemic. This information will allow us to better understand of the pandemic's impact on the pediatric kidney transplant population.

Data Source
This study used data from the Scienti c Registry of Transplant Recipients (SRTR). The SRTR data system includes data on all donor, wait-listed candidates, and transplant recipients in the US, submitted by the members of the Organ Procurement and Transplantation Network (OPTN). The Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors. This dataset has previously been described elsewhere [20].

Study Population
For waitlist analysis, we included DDKT waitlist registrants aged 0-17 at time of listing (new listing; changed to inactive status; removed due to DDKT, LDKT, death or deteriorating condition, and other causes) were included. For analysis of transplant volume (DDKT, LDKT, DCD, national or regional import) recipients aged 0-17 at time of transplant were included.

National cumulative incidence of COVID-19
National COVID-19 incidence data from January -June 2020 were extracted from USA FACTS (https://usafacts.org/issues/coronavirus/) [21]. COVID-19 incidence is reported for all patients and not restricted to children, as many states are not providing data of infections by age groups. Based upon cumulative incidence of COVID-19 positive cases per-million state population (PMP) between March 15 and June 30, states were strati ed to be having low (<8000 PMP) or high (>8000 PMP) COVID-19 burden. This cutoff was selected based on an visible difference in distribution of cumulative incidence of COVID-19 burden in the United States.

Weekly counts of waitlist and transplant changes
For each week (Sunday-Saturday) starting February 2, 2020 until June 27, 2020, we plotted cumulative counts of new waitlist additions, newly inactive patients, waitlist removal due to death or deteriorating condition, and waitlist removal due to transplant or other causes, using a Lowess smoothing function. We made similar plots for weekly counts of DDKT, LDKT, DCD donor, and regional and national imports. Weekly instead of daily counts were used due to the low number of daily events in pediatric patients to enable statistical analysis. On each plot we also included the average counts during the same period in 2017-2019 as a visual reference of national pre-pandemic pediatric KT volume.

Statistical analysis
We presented characteristics of pediatric kidney transplant recipients separately in three time periods: January 1 -March 15, 2020 ("Early"); March 16 -April 30, 2020 ("Middle"); and May 1 -June 30, 2020 ("Late"). Continuous variables were presented as median and interquartile range, and categorical variables were presented as counts and proportion. Comparison between groups were tested using Kuskal-Wallis or Mann Whitney-U, as appropriate, for continuous variables and Fisher's exact test for categorical variables. We used 2015 as reference year to calculate KDPI [22]. We obtained pediatric kidney waitlist changes or transplant volume by center, month and year from January 1, 2016 to February 28, 2020, and constructed a mixed-effects Poisson regression with a center-level random intercept to obtain expected daily counts by center (monthly counts divided by 31), using methods previously described [23]. The expected counts of each time period were the sum of expected center-level counts during the corresponding length of time (March 1 to April 30: 47 days; May 1 -June 30: 61 days). We then compared the observed and expected counts of each time period using Chi-square testing. We used an α of 0.05 to de ne statistical signi cance. All analyses were performed using Stata 16.0/MP for Linux (College Station, Texas).

Characteristics of pediatric transplant patients during COVID-19
Patient characteristics in three time periods ("Early" Jan 1 -Mar 15 2020, "Middle" Mar 16 -Apr 30 2020, and "Late" May 1 -Jun 30 2020) were examined (Table 1) Weekly count of waitlist changes National weekly pediatric KT waitlist additions ranged from 7 -41 cases per week between February 2 and June 30, 2020. There was a trend of decreasing new pediatric DDKT registrations, following the national rise of COVID-19 cases mid-March. Since April, none of the weekly pediatric KTs exceeded 21, the 2017-2019 average counts for the same period ( Figure 1A). The numbers of registrants who changed to inactive status also increased in March, with 77.2% of registrants who changed to inactive status in the third and fourth week of March indicating COVID-19 as reason of inactivation ( Figure 1C). COVID-19 was added as a refusal code or cause for change in status in UNET on March 25, 2020; however, this classi cation does not differentiate new COVID-19 infection in the patient vs precaution secondary to the pandemic.
Percentage of inactive waitlist registrants rose from 72% to 77% between March 1 and April 15, and remained elevated above previous baseline thereafter ( Figure 1D). We observed an increasing trend in waitlist removal due to death or deteriorating condition since March, followed by a trend that returned to previous benchmarks by late-April ( Figure 1B).

Weekly count of transplant events
The national weekly pediatric DDKT volume ranged from 0-16 cases per week between February 1 and June 30, 2020.
On average, the weekly DDKT volume in 2017-2019 was 9.6 cases. Between mid-March and the end of June 2020, DDKT volume remained lower than 9.6 except for 4 weeks out of the 15 during observation. There was a trend of decreasing DDKT and LDKT volume seen since March, followed by increase from mid-April to end of June (Figure 2A,   2B). For LDKT, the weekly volumes were never above the 2017-2019 average between mid-March and May 31, but consistently surpassed this volume in June 2020 ( Figure 2B).

Regional and National Imports
Overall numbers of regional and national imports were extremely low (0-4 per week), with average <1 import per week in 2017-2019 ( Figure 2C). During the early period of COVID-19 disease activity in the United States, imports were more common than in previous years. As the pandemic progressed, there was a decline in imports, however the average number of imports continue to remain higher than previous years.

Comparing the observed and predicted waitlist changes
The overall observed national volume of waitlist registration was lower (-13.3%, p=0.021) and change to inactive waitlist status was higher (57.2%, p<0.001) compared to the expected volume during March 15 -June 30, 2020 (Table  2). When strati ed into the earlier (March 15 -April 30, 2020) and the latter (May 1-June 30, 2020) periods, 6 candidates were removed from the waitlist during the earlier period due to death or deteriorated condition, which was 189% more than the expected 2.1 cases (p=0.005). Similarly, 83 candidates had changed to inactive status during the earlier period, which was 152% more than the expected 32.9 cases (p<0.001). In both cases, the signi cance was not achieved in the latter period (11.3%, p=0.3 and -11.1%, p=0.5, respectively). Contrarily, the observed counts of new waitlist registration was 23.8% lower compared to the expected during the latter period (p=0.002), though not signi cantly different in the earlier period (0.4%, p=1.0).

Discussion
In this national registry study of pediatric KT trends during the COVID-19 pandemic, we found an increase in patients being changed to inactive status by 152%, increase in mortality on the waitlist by 189%, decrease in DDKT by 48% and LDKT by 82% compared to expected in the early COVID-19 time period without a signi cant impact on new waitlist additions. The COVID-19 pandemic has substantially limited access to KT and increased waitlist mortality in pediatric patients.
Many transplant programs signi cantly altered their routine protocols and stopped performing kidney transplants thereby restricting access to KT during the COVID-19 pandemic [4]. A recent registry of adult SOT recipients infected with COIVD-19 did not show any signi cant difference in mortality or morbidity compared to non-SOT patients [24].
While extensive data in pediatric solid organ transplant (SOT) recipients is not available, several case reports show that pediatric SOT patients infected with COVID-19 showed only mild disease, even while on immunosuppressive therapy [25,26]. As children have different etiologies of ESRD, different comorbidities and seem to be affected differently by COVID-19, uniform policies affecting access to transplantation for both children and adults are not appropriate nor in the best interest of pediatric patients [16]. The increased mortality while on the waitlist that we showed in pediatric patients is a striking metric that supports the need for an individualized approach for pediatric KT patients. As pediatric KT events are relatively rare compared to adult KT, this affords an opportunity for patient-level versus center-level decisions about risk and bene t of KT in a pandemic setting.
The reduction of transplant events in children seen during the Middle (March 15 -April 30, 2020) COVID-19 era was likely secondary to a combination of factors. As hospitals shifted resources to treat COVID-19 patients there was a decrease in available ICU beds for post-operative management and restrictions on operating room availability. Pediatric KT patients require intensive post-operative care, which may strain healthcare systems already overburdened by COVID-19 patients [27]. In addition, there was a notable decline in deceased donor organs recovered during March and April [28]. Shortages of COVID-19 testing or delayed results for deceased donors may have impacted center willingness to accept an organ from what would otherwise be an acceptable donor. As testing capacity increased across the country, this limitation was ameliorated. Finally, many centers stopped or signi cantly reduced elective and non-emergent surgical procedures, which likely had a signi cant impact on LDKT. For pediatric patients scheduled to receive an LDKT, it should be argued that transplant is not truly an elective procedure whether pre-emptive or not. Dialysis initiation would require at least one surgical procedure to establish dialysis access, and initiation or continuation of hemodialysis would result in a much higher COVID-19 exposure risk [29].
While peritoneal dialysis patients do not require frequent in-center visits and thereby can have minimal healthcare exposure, especially with the advancement of telehealth capabilities across the country, the bene t of transplant over dialysis has been well established in the pediatric ESRD population [30,31]. As healthcare centers lifted restrictions on elective cases and practice patterns changed, there was a large increase in LDKT in June 2020 suggesting cases had been postponed due to the pandemic.
Our hypothesis that children who received a transplant during the peak of the pandemic would differ in some characteristics compared to pre-pandemic patients was not supported. There was not a statistically signi cant difference in donor KDPI, recipient cPRA, or etiology of ESRD. While cold ischemia time in the Middle time period was longer, this is unlikely to be a clinically signi cant difference. This is the rst study to describe characteristics of donors and recipients receiving a KT during the pandemic.
As this is a registry study, we are limited in the information that is available for analysis and are not able to delve into granular details of waitlist removal or patient death. While transplant centers have mandatory reporting requirements to UNOS/OPTN, data transmission may be delayed due to center practices and pandemic effect on work ow. Nevertheless, we are able to make generalized conclusions about the effects of COVID-19 on access to KT in pediatric patients. We were unable to differentiate regional variability in transplant rates and waitlist changes due to the overall low number of events in pediatric patients.
In summary, we found that the COVID-19 pandemic has had a signi cant impact on pediatric KT waitlist mortality, waitlist registration, DDKT and LDKT. Further studies to assess outcomes of pediatric patients who received a KT during this time are necessary to inform changes in policies and practices to optimize pediatric transplant outcomes and ensure access to this life-saving treatment.