EXPERIMENTAL AND CLINICAL TRANSPLANTATION

The COVID-19 pandemic has become a profound health crisis, greatly affecting the general population across the world. Presently, there have been more than 100 million confirmed cases and over 3 million deaths. Patients treated with kidney replacement therapy (either kidney transplant or dialysis) have potential risk factors for worse COVID-19 outcomes as they are usually older with significant comorbidities and impaired immune responses. The COVID-19 pandemic has had a huge influence on transplantation because many transplant centers have had to reduce or suspend their programs in response to decreased organ donations and anecdotal reports of poor outcomes in transplant recipients. Although it has long been recognized that kidney transplant recipients have a better prognosis than patients on dialysis, transplant recipients need combinations of immunosuppressive drugs, which made them more susceptible to infections with respiratory viruses. Whether those with COVID-19 still have better outcomes remains controversial. Thus, we conducted a systematic review and meta-analysis to compare the clinical outcomes between kidney transplant recipients and patients on dialysis with COVID-19.

Databases (PubMed, Cochrane Library, Embase, Web of Science, VIP Database of Chinese periodicals, and China National Knowledge Infrastructure) were systematically searched for relevant studies without any language restrictions. We used the keywords “kidney transplant” or “dialysis” or “kidney replacement therapy” AND “novel coronavirus” or “coronavirus disease 2019” or “SARS-CoV-2” or “COVID-19” for our search with publication dates from January 1, 2019, to April 20, 2021. Studies were included if they fulfilled our inclusion criteria: (1) studies that included patients with COVID-19 infection and (2) studies with relevant data regarding comparisons of clinical outcomes between kidney transplant recipients and patients on dialysis with COVID-19. Studies were excluded if (1) they did not make comparisons between kidney transplant and dialysis (survival versus death, nonsevere versus severe) and if (2) they were conference abstracts, case reports, reviews, letters to the editor, or comments.

We extracted the following information from each retrieved article: first author of the study, country of study, follow-up duration, study design, type of dialysis, age, numbers of men and women, and outcomes of interest. The severity of COVID-19 was mainly based on clinical manifestations (eg, patients in need of mechanical ventilation or admitted to the intensive care unit with acute respiratory distress syndrome). Two researchers (FL and GA) analyzed the quality of studies according to the Newcastle-Ottawa Scale. A total score of 7 or greater indicated a high-quality study, whereas a total score of <7 indicated a low-quality study.

Two investigators (YW and FL) independently conducted the literature search, study selection, and data extraction. Any disagreements were resolved by consensus discussion with a third author (XQ). Statistical heterogeneity among studies included in the meta-analysis was analyzed by Cochran’s Q statistic and the I² metric. Studies with an I² value less than 25%, 25% to 50%, and greater than 50% were considered as indicators of low, moderate, and substantial heterogeneity, respectively. A fixed-effects model was used to calculate the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) if heterogeneity was substantial; otherwise, the random-effects model was used. If possible, we used adjusted hazard ratios (HRs) for estimates of the overall effects. We also conducted a sensitivity analysis in which the individual study was excluded to examine the influence of a specific study on the overall results. The data were analyzed using Review Manager 5.3 (Cochrane Collaboration) and Stata version 15.0 (Stata Corp). P < .05 was considered to be statistically significant. This research is registered with PROSPERO (number CRD42021253924).

The literature search initially identified 485 publications. Of these, only 13 studies involving 11 291 participants met our inclusion criteria and were included in the pooled analysis.^1-13 Among the studies, there were 2641 kidney transplant recipients and 8650 patients on dialysis. The sample sizes ranged from 21 to 4298 patients per study. Five studies included patients on hemodialysis, whereas other studies included both patients on hemodialysis and on peritoneal dialysis. All studies were from European countries, with 5 of these from the United Kingdom. Only 1 study was prospective, whereas the others were retrospective. Table 1 shows the characteristics of these 13 studies. The quality score of these studies ranged from 7 to 8.

We found no differences between kidney transplant recipients and patients on dialysis with regard to development of severe COVID-19 (OR = 1.42; 95% CI, 0.74-2.73; P = .29, I2 = 57%) (Figure 1A). When we restricted the analysis to studies that only included patients on hemodialysis, we observed no differences between kidney transplant recipients and patients on dialysis with regard to development of severe COVID-19 (OR = 0.98; 95% CI, 0.55-1.75; P = .95), without any heterogeneity (I2 = 0%). Furthermore, pooled analysis of unadjusted results showed that kidney transplant was associated with a decreased risk of COVID-19-related mortality compared with dialysis (OR = 0.89; 95% CI, 0.80-0.99; P = .04, I2 = 0%) (Figure 1B). However, pooled analysis of adjusted results from 4 studies^3-5,8 indicated no differences in mortality between kidney transplant and dialysis (HR = 1.57, 95% CI, 0.92-2.67; P = .10, I2 = 85.7%) (Figure 1C). Sensitivity analyses, by removing any single study at a time, did not significantly change the results.

Chronic kidney disease and immunosuppression are the established potential risk factors for severe COVID-19. Our meta-analysis of unadjusted results showed that kidney transplant recipients had lower risk of mortality than patients on dialysis. However, our meta-analysis of adjusted results provided similar results in mortality between kidney transplant recipients and dialysis patients. A recent study suggested that transplant recipients with COVID-19 have higher rates of intensive care unit admissions and hospital mortality.¹⁴ Our previous study found that solid-organ transplant recipients with COVID-19 had greater severity and higher mortality than the general population.¹⁵ Long-term use of a variety of immunosuppressive agents made them more susceptible to infection, even bacterial and fungal coinfections. In addition, because of the side effects of immunosuppressive drugs, organ transplant recipients are more susceptible to development of acute kidney injury, which was associated with an increased risk of morality. For patients on dialysis, uremia is a state of chronic immunosuppression and chronic immune activation. Because of the disorder of natural and adaptive immunity, the risk of infection in patients on dialysis increases. Increased production and decreased clearance of proinflammatory cytokines can cause inflammation and extracellular volume disturbances, perhaps affecting their prognosis. In addition, patients on dialysis are more likely to be older and with significant comorbidities, which places them at higher risk of severe illness. Although we found no difference in COVID-19-related mortality between kidney transplant recipients and patients on dialysis, the benefits of kidney transplant should not be ignored during this pandemic, given the overall importance to improve the quality of life of dialysis patients.

There are several limitations to our present meta-analysis. First, the included observational studies were affected by potential confounding factors. Significant heterogeneity was observed among the included studies. However, it was not possible to evaluate the sources of heterogeneity comprehensively, since the baseline characteristics of some studies were not available. Second, the total number of patients was relatively small, which may weaken the overall effect estimate. In addition, our meta-analysis of adjusted results of mortality was based on only 4 studies. The substantial heterogeneity across the studies could be due to different definitions of severe COVID-19 and type of dialysis. However, we could not conduct further subgroup analysis based on these factors because of the limited data available.

In conclusion, our meta-analysis revealed that kidney transplant recipients may have COVID-19 outcomes similar to patients on dialysis. As services start to recover and more and more people get vaccinated, both transplant centers and patients on dialysis should start planning for transplant, especially for patients with suitable donors.

Volume: 20 Issue: 3 March 2022

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