key: cord-0784074-zogxadr9
authors: Malinowska, Agnieszka; Heleniak, Zbigniew; Muchlado, Marta; Ślizień, Zuzanna; Ruszkowski, Jakub; Tylicki, Leszek; Król, Ewa; Dębska-Ślizień, Alicja
title: Changes in kidney graft function in COVID-19 convalescents.
date: 2022-03-16
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2022.03.003
sha: a7aef507de7d681048dee291dc365ef933357b20
doc_id: 784074
cord_uid: zogxadr9

Introduction Kidney transplant recipients (KTR) are at an increased risk of infection with severe respiratory syndrome coronavirus 2 (SARS-CoV-2) with mortality from 13 to over 30%. However, data concerning the influence of COVID-19 on long-term graft function in convalescents is lacking. Material and Methods A longitudinal controlled study was conducted in a group of 1058 KTR. Of 180 patients with COVID-19 in the past, 77 KTR (45 male) at a mean age 50.57±13.37 years, Charlson Comorbidity Index (CCI) of median (interquartile range - IQR) 3(3-5), Fragility Score (FS) of median (IQR) 3(3-3) and minimum 6 months after acute COVID-19 were included. The most common symptoms were: weakness (75.33%), fever (74.03%), cough (51.95%), and loss of appetite (48.05%). 33 of them were hospitalized, no one required invasive ventilation therapy, but 16 required oxygen support. The treatment of COVID19 included antibiotics (38.96%), thromboprophylaxis (25.97%), NSAIDs or paracetamol (25.97%). The aim of the study to evaluate the influence of COVID-19 on graft function at 6 months after recovery. Results The median (IQR) values of serum creatinine 3 months before the onset and 6 months after COVID19 were: 1.25(0.98-1.86) and 1.26(1.03-1.78) mg/dl (non-significant difference); in strata analysis, there were also no differences with regards to patients with higher and lower comorbidity (3<CCI<3) and fragility (3<FS<3). Furthermore, creatinine concentration in KTR and controls did not differ. Conclusion In the group of KTR with a mild course of COVID-19 no negative impact of the infection on graft function was noticed 6 months after recovery.

COVID-19, caused by SARS-CoV-2, has several manifestations. The most common manifestation is respiratory failure, but acute kidney injury is also widespread. Some reports showed evidence of viral tropism to the renal system 1 . The exact mechanism of virus-associated kidney damage is not fully known. The pathophysiology of this phenomenon can be explained by multiple mechanisms. A direct damaging factor may be the binding of the spike protein to ACE2, endothelial dysfunction, coagulopathy or -cytokine storm‖. An intermediate cause of renal failure may include the systemic effects of COVID-19, such as volume depletion due to fever or gastrointestinal symptoms, nephrotoxic medications 2 . Acute kidney injury (AKI) may be a complication of COVID-19 in KTR, not only due to the severity of systemic viral infection and the treatment itself, but also due to direct mechanisms like glomerulopathy, endothelial dysfunction, complement activation, coagulopathy including thrombotic microangiopathy 3 . Renal impairment in COVID-19 is associated with increased mortality 4 . Depending on the study population, the fatalities ranged from 13% 5 to over 30% [6] [7] [8] . Kidney transplant recipients (KTR) are a special group at an increased risk of infection due to immunosuppression and pre-existing renal impairment. The risk of SARS-CoV-2 infection and complications in KTR remains high today, even after widespread vaccination against COVID-19. As our previous studies have shown, the immune response and humoral protection appear in a limited form only in about half of the vaccinated KTRs 9, 10 Data concerning the influence of COVID-19 on long-term health consequences in KTR is scarce.

The aim of the study was to evaluate the impact of SARS-CoV-2 infection on graft function at 6 months after recovery.

An observational longitudinal controlled study was conducted in a group of 1058 kidney transplant patients under the care of our department. They were screened between the 1st of January to the 1st of June for a history of COVID-19. All cases of COVID-19 were diagnosed before the vaccination was initiated. We excluded the following patients: 1, who did not agree to take part in the study; 2, in whom COVID-19 was not confirmed with RT-PCR tests from nasopharyngeal/oropharyngeal swabs, antigen tests or elevated levels of SARS-CoV-2 IgG antibodies; 3, who died within 6 months of infection; 4, whose creatinine level was not measured in the laboratory of Clinical University Center either before or 6 months after infection (Fig. 1) . The control group consisted of kidney transplant recipients who have not been diagnosed with COVID-19, of the same age and sex, with similar comorbidities and fragility. Ethics approval for the study was obtained at the Medical University of Gdańsk (NKBBN/2014/2021). The study is part of the ‗COVID-19 in Nephrology' project focusing on the nephrological aspects of COVID-19 (COViNEPH).

KTR were interviewed retrospectively for COVID-19 symptoms and treatment. Other information about demographic and clinical characteristics, comorbidities according to the Charlson Comorbidity Index 11 , was obtained from the electronic patient data. The level of clinical frailty was calculated with the Clinical Frailty Score before, and 6 months after, COVID-19 recovery retrospectively for all the participants. The Rockwood Clinical Frailty Scale is a judgement-based tool with scores from 1-9, where 1 = very fit, active and motivated; 2 = well, no active disease symptoms, active occasionally; 3 = managing well, medical problems are well-controlled, not regularly active; 4 = vulnerable, not dependent on others for daily help, symptoms limit activities; 5 = mildly frail, more evident slowing, need help in finances, transportation, heavy housework, medications; 6 = moderately frail, need help with all outside activities and with keeping house; 7 = severely frail, completely dependent for personal care; 8 = very severely frail, completely dependent, approaching the end of life; 9 = terminally ill, people with life expectancy < 6 months, who are not otherwise evidently frail. Patients scored at 1-3 on the FS are defined as not frail. Participants from the control group were screened retrospectively for a non-positive RT-PCR SARS-CoV-2 test during the observation period. Creatinine serum concentrations were measured using an enzymatic method during regular visits to the outpatient clinic; eGFR was calculated according to the CKD-EPI formula.

Descriptive statistics were used to report the characteristics of patients. Normally distributed values were shown as mean ± standard deviation (SD), those abnormally distributed as median (IQR). The main outcome measure was an increase or decrease in creatinine levels of patients after COVID-19.

T-tests or Wilcoxon signed rank tests were used to compare continuous variables where appropriate. P < 0.05 was considered statistically significant. Data was evaluated using the STATISTICA (version 12.0 Stat Soft INC.) software package.

Of 1058 KTR screened, 180 had COVID-19 symptoms in their history. The patient enrolment process is presented in the flowchart in 

There were no significant changes in the graft function before and after COVID-19, neither in the median level of creatinine (1.25 vs. 1.26 mg/dl) nor eGFR CKD-EPI results (61 vs. 58 ml/min/1.73m 2 ).

The differences were also negligible in the control group, with a median creatinine level 1.28 mg/dl in the beginning, and 1.29 mg/dl after 6 months of the observation period. Details are presented in Table   2 .

To our knowledge, this is one of the first studies to evaluate long-term graft function in KTR after SARS-CoV-2 infection. Although we know that the serious sequelae of the disease extend beyond the acute phase of COVID-19 12 , we have not seen statistically significant changes in serum creatinine levels in this group of patients.

In fact, most of the publications are mainly based on in-patient cohort studies and are related to the acute phase of the infection. In a paper from the first few months of the pandemic, even 45% of patients presented with acute allograft dysfunction, which highlighted the impact of SARS-CoV-2 infection on kidney function. However, the median follow-up time from presentation was only 25 days (IQR 13-38) 13 , the long-term impact of COVID-19 on kidney function was unclear. In the other few published articles, a cohort study with 104 KTR showed that although allograft function remained stable after acute COVID-19 in most patients, after 6 months two of them were dialysis-dependent, and two had reached the preterminal stage of chronic allograft nephropathy without dialysis 14 .

It is worth underlining that graft function remained stable during the COVID-19 infection in the subpopulation of KTR with the highest comorbidity index (CCI≥3). Moreover, graft function did not change statistically significantly in the most frail subpopulation, which scored above 3 in the clinical frailty scales (FS>3). The percentage of patients with FS above 3 increased from 15.58% to 25.97% after 6 months of the COVID-19 infection. That rise points to the necessity of an early start for physiotherapy and the rehabilitation of post-COVID-19 convalescents.

Our study has limitations: this is a single-center study with a small sample size. Therefore, our results need to be validated by larger prospective cohort studies. Second, we had no information on graft function during coronavirus infection. Certainly, some cases of acute allograft dysfunction had to occur during the early phase of infection and shortly after. We also cannot eliminate some degree of underreporting of COVID-19 in KTR. Thirdly, as the heaviest limitation, we had to exclude 36 patients from our analysis due to withdrawal of consent and a lack of serum creatinine measurement in our center. The reason for the drop-out of KTR from our observation was mainly caused by the patient's fear before any medical contact during the epidemic. However, since there were no significant differences in age and sex between study population and all patients excluded from our analysis, we believe that the selection bias was unlikely. It seems to be interesting to compare kidney function with non-transplant recipients, with similar degree of comorbidity and frailty as well, who suffered from COVID-19. Additionally, further studies focused on the long-term outcomes of COVID-19 and monitoring of all patients who survived the infection are needed.

In conclusion, our analysis reveals that in the group of KTR with a mild course of COVID-19 no negative impact of the infection on graft function was noticed 6 months after recovery.

Katz-Greenberg G, Yadav A, Gulati R, Singh P. Outcomes of COVID-19-positive kidney transplant recipients. J Am Soc Nephrol. 2020;31.

14.

Basic 

The kidney and COVID-19 patients -Important considerations

COVID-19 impact on the renal system: Pathophysiology and clinical outcomes

Thrombotic microangiopathy in a kidney transplant patient after COVID-19

Renal impairment and its impact on clinical outcomes in patients who are critically ill with COVID-19: a multicentre observational study

COVID-19 in kidney transplant recipients: A multicenter experience in Istanbul

Kidney transplant patients with SARS-CoV-2 infection: The Brescia Renal COVID task force experience

COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter

Predictors of humoral response to mrna covid19 vaccines in kidney transplant recipients: A longitudinal study-the covineph project

Boosting Humoral Immunity from mRNA COVID-19 Vaccines in Kidney Transplant Recipients

A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation

Post-COVID-19 sydrome and decrease in healthrelated quality of life in kidney transplant recipients after SARS-CoV-2 infection-a cohort longitudinal study from the north of poland