Objectives: Growing evidence has highlighted the substantial effects of COVID-19 on kidneys, ranging from mild proteinuria to severe acute kidney injury. However, comprehensive assessments of histopathological features in renal allograft biopsies are lacking.
Materials and Methods: Seventeen kidney transplant recipients with COVID-19 between March 2020 and November 2022 were evaluated. Clinical characteristics, pathological findings, and outcomes were studied.
Results: Six kidney transplant recipients (35.3%) developed acute kidney injury, leading to the requirement for hemodialysis. COVID-19 severity, as indicated by pneumonia (P = .028) and hospitalization (P = .002), was significantly associated with development of acute kidney injury. Most patients with COVID-19 (82.4%) showed considerably increased proteinuria levels (82.4%), along with presence of new-onset microscopic hematuria (35.3%) and nephrotic syndrome (58.8%). Tubular viral inclusion-like changes were detected in 47.1% of cases and were associated with a higher risk of graft loss (75%). Thrombotic microangiopathy and endothelial cell swelling in glomeruli were prevalent, highlighting extensive endothelial cell injury. Most recipients (88.2%) experienced rejection after COVID-19, with graft loss occurring in 46.7% of these cases. Biopsies revealed collapsing (n = 5), noncollapsing (n = 3), and recurrent (n = 2) focal segmental glomerulosclerosis, as well as acute tubulointerstitial nephritis (n = 3), crescentic glomerulonephritis with immunoglobulin A nephropathy (n = 1), and membranoproliferative glomerulonephritis (n = 1), in 129.7 ± 33 days. Eight patients experienced graft loss (8.2 ± 2 mo posttransplant). Hospitalization (P = .044) and viral-inclusion-like nuclear changes in tubules (P = .044) significantly influenced graft survival. Collapsing (60%) and noncollapsing (66.7%) focal segmental glomerulosclerosis increased the risk of graft loss.
Conclusions: COVID-19 has had a multifaceted and enduring effect on renal allografts, urging the need for meticulous monitoring and tailored management strategies to mitigate the risk of severe kidney-related complications and graft loss in this vulnerable population.

Key words : Acute kidney injury, Glomerulopathy, Graft survival, Kidney, Rejection, SARS-CoV-2, Transplantation

Introduction

The outbreak of the novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly evolved into a global pandemic, challenging health care systems worldwide and presenting significant health care challenges.^1-4 Respiratory symptoms primarily characterize coronavirus disease, but various clinical manifestations can be shown that affect multiple organ systems beyond the respiratory tract, including the kidneys.^1-4

SARS-CoV-2 belongs to the coronavirus family, encompassing enveloped RNA viruses known for infecting animals and humans. The virus primarily targets the respiratory tract and utilizes the angiotensin-converting enzyme 2 (ACE2) receptor as its entry point into host cells.^1,3 COVID-19 showcases a broad spectrum of clinical presentations, ranging from asymptomatic or mild to severe respiratory distress and multiorgan failure. Common symptoms include fever, cough, and shortness of breath, often accompanied by fatigue, muscle aches, and loss of taste or smell. However, unique to COVID-19 is its ability to manifest atypically, including gastrointestinal symptoms such as diarrhea, nausea, and vomiting, as well as neurological manifestations like headache and confusion.^2-5

The clinical course of COVID-19 varies widely among individuals. Although many people expe-rience mild symptoms and recover without hospitalization, others deteriorate rapidly into severe pneumonia and acute respiratory distress syndrome. Advanced age and underlying medical conditions, such as hypertension, diabetes, cardiovascular disease, end-stage renal disease, and transplantation, are associated with increased disease severity and mortality. Cytokine storms, an exaggerated immune response, may contribute to the severe manifestations observed in some patients.^2-4 Among vulnerable populations exposed to heightened risks associated with SARS-CoV-2 infection, kidney transplant recipients (KTRs) emerge as a particularly high-risk group because of their immunocompromised status resulting from lifelong immunosuppressive therapies and underlying renal compromise.^6,7

Kidney transplantation is a transformative inter-vention for patients with end-stage renal disease, offering a new lease on life with enhanced quality and longevity. However, the intricate balance between immunosuppression and immune surveillance renders KTRs susceptible to opportunistic infections, making them a high-risk cohort during the COVID-19 pandemic. The interaction between COVID-19 and the transplanted kidney can be particularly complex as a result of immunosuppressive drugs and the altered immune response in KTRs. The emergence of SARS-CoV-2 has introduced unique challenges for KTRs, necessitating a thorough exploration of the intersection between COVID-19 and kidney transplantation.^6,7

Renal involvement is a recognized complication in COVID-19 patients. Renal manifestations in COVID-19, including acute kidney injury (AKI), proteinuria, hematuria, and other renal abnormalities, are associated with increased morbidity and mortality.^8-10 Histopathological examination of renal tissue provides valuable insights into the mechanisms and manifestations of renal injury associated with the disease. The mechanisms by which SARS-CoV-2 affects the kidneys are not yet fully understood but are thought to involve direct viral invasion, endothelial dysfunction, immune-mediated injury, and cytokine storm.^8-10 These insights highlight the multifaceted effects of SARS-CoV-2 on renal tissue, ranging from acute tubular injury (ATI) to glomerular pathologies and immune-mediated changes. Understanding the mechanisms underlying renal injury in COVID-19 is crucial for appropriate management and improving patient outcomes.

Histopathological analyses of kidney biopsies from COVID-19 patients have unveiled a complex array of renal findings, encompassing glomerular, tubulointerstitial, vascular, and other histological abnormalities.^8-14 Among these pathologies, patients have shown a high incidence of ATI.^8-10,11

As KTRs navigate the complexities of COVID-19, understanding the intricate interplay among viral infection, immunosuppression, and graft function becomes imperative. In this study, we have delved into the multifaceted relationship between COVID-19 and kidney transplant, investigating the effect of the virus on KTRs’ clinical presentation, renal complications, immunological responses, and graft outcomes. By dissecting the available data and research, we aim to shed light on the specific vulnerabilities that KTRs face with COVID-19 and the subsequent implications for clinical management and graft survival.

Materials and Methods

We assessed 17 KTRs who had confirmed SARS-CoV-2 infection who were seen at a single center (Baskent University) between March 2020 and November 2022. SARS-CoV-2 infection was confirmed in all patients by reverse transcriptase-polymerase chain reaction assay. All patients underwent triple immunosuppressive therapy comprising calcineurin inhibitors, mycophenolate mofetil, and corticosteroids. We evaluated the clinical and laboratory findings, as well as the outcomes, of each KTR.

We conducted histopathological examinations of renal allograft biopsy samples to assess renal tissue damage. At least 2 biopsy cores were obtained from each KTR for light microscopy, and 1 biopsy core was obtained for immunofluorescence analysis. All biopsies were performed based on indications arising from new-onset proteinuria, hematuria, and elevated creatinine or proteinuria levels. We fixed the renal allograft biopsy cores for light microscopy in 10% buffered formalin and processed samples using standard techniques. Fresh renal biopsy cores were frozen at optimal cutting temperature, and thin slices were sectioned for immunofluorescence analysis. We then incubated sections with primary antibodies targeting specific antigens, including immunog-lobulin G (IgG), IgA, IgM, complement components (C3c, C4c, C4d), and other relevant proteins.

We assessed the occurrence of rejection during and after COVID-19 infection. The average time for the development of T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) after COVID-19 infection was documented for all KTRs. We used Banff classification to score all biopsies. Furthermore, we evaluated declines in renal allograft function and other complications associated with graft loss and patient outcomes.

This study was approved by the Baskent University Institutional Review Board and Ethics Committee. The reported data are consistent with the Principles of the Declaration of Istanbul outlined in the Declaration of Istanbul on Organ Trafficking and Transplant Tourism. Individual-level informed consent was not obtained as the data were collected retrospectively.

Statistical analyses
We used IBM SPSS software (version 25.0) for statistical analyses. All values are presented as mean ± SE. We compared mean values of quantitative data by using analysis of variance. We evaluated categorical variables with the Pearson chi-square test or the Fisher exact test. We used the Spearman correlation test to analyze correlations between quantitative data. P < .05 was considered significant.

Results

In our cohort of 17 KTRs diagnosed with SARS-CoV-2 infection, the mean age was 36.3 ± 3.6 years. Table 1 presents demographic, laboratory, and clinical characteristics of study patients. Nearly all KTRs (94%) were male, and most KTRs (88.2%) received their allografts from living related donors. The mean time between transplant and last follow-up was 76.9 ± 11.6 months, and the mean follow-up time after COVID-19 was 16.4 ± 2.3 months (range, 3-36 months).

Kidney transplant recipients presented with initial symptoms of fever (94.1%), cough (58.8%), diarrhea (35.3%), and shortness of breath (11.8%). These symptoms are consistent with the presentation of COVID-19 in the general population. Only 5 KTRs (29.4%) developed pneumonia and needed hospita-lization. In total, 8 KTRs were hospitalized at an average of 9.6 ± 1.8 days. The mean hospitalization time was 10.8 ± 2.5 and 7.6 ± 2.6 days for KTRs with and without pneumonia, respectively.

The mean baseline serum creatinine, mean creatinine level at the time of COVID-19, mean creatinine level at the time of the index biopsy, and the mean follow-up creatinine level after the index biopsy were 1.28 ± 0.1, 2.7 ± 0.4, 2.9 ± 0.3, and 3.9 ± 0.6 mg/dL, respectively (Table 1). Among the 17 KTRs, 10 (58.8%) had a history of hypertension and 7 (41.2%) had a history of diabetes mellitus. Tacrolimus (n = 11, 64.7%) was the most common immunosuppressive medication; the other 6 patients received cyclosporine A therapy.

Of 17 KTRs, 6 (35.3%) developed AKI during COVID-19 infection, and all of these patients required hemodialysis treatment. The development of AKI was associated with increased disease severity, as evidenced by the presence of pneumonia (P = .028), hospitalization (P = .002), and the necessity for hemodialysis treatment (P < .001). The incidence of TCMR and ABMR after COVID-19 infection in patients with AKI was 33.3% (n = 2/6) and 66.7% (n = 4/6), respectively. The rates of thrombotic microangiopathy (TMA), endothelial cell (EC) swelling in glomeruli, and nuclear viral inclusion-like changes in tubules of KTRs with AKI were 66.7%, 33.3%, and 50%, respectively. Graft loss occurred in 66.7% of patients (n = 4/6) with AKI; the mean graft survival was 9 ± 4.3 months for KTRs with graft loss. The remaining 2 patients maintained functioning grafts throughout the follow-up period.

Before COVID-19, only 7 KTRs (41.2%) had proteinuria at a mean of 712 ± 67 mg/day. The level of proteinuria increased to 3890 ± 413 mg/day in these 7 patients after development of COVID-19. After COVID-19, 14 KTRs (82.4%) displayed significant proteinuria (3366 ± 334 mg/day) during follow-up. Moreover, 6 KTRs (35.3%) had new-onset microscopic hematuria. Ten KTRs (58.8%) developed new-onset nephrotic syndrome. None of the patients had nephrotic-range proteinuria before COVID-19. These significant differences in proteinuria levels before and after COVID-19 infection indicate the potential effects of the virus on renal function. Therefore, all KTRs had renal allograft biopsies after COVID-19 infection at an average time of 129.7 ± 33 days (range, 11-550 days).

On histopathological examination, a substantial proportion (82.4%) of KTRs displayed varying degrees of ATI features, highlighting the direct effect of the virus on renal tissue. Notably, viral inclusion-like changes were observed in the nuclei of tubular cells in 47.1% of cases (n = 8), further emphasizing the viral-induced damage (Table 2). Cytomegalovirus, polyomavirus serology, and immunohistochemistry examinations were negative in all KTRs, especially in cases with viral inclusion-like changes. The risk of graft loss was higher (75%) in patients with tubular inclusion-like changes (P < .05). After COVID-19 infection, KTRs with tubular inclusion-like changes lost their graft at 5.6 ± 0.8 months, whereas patients without these changes lost their graft at 16 ± 6 months (P = .001).

Of 6 KTRs with ATI during COVID-19 infection, 4 (66.6%) demonstrated histological features of acute tubular necrosis in index biopsies. In addition, biopsies showed collapsing focal segmental glomerulosclerosis (FSGS) in 5 KTRs, noncollapsing FSGS in 3 KTRs, FSGS recurrence in 2 KTRs, acute tubulointerstitial nephritis in 3 KTRs, crescentic glomerulonephritis with IgA nephropathy in 1 KTR, and membranoproliferative glomerulonephritis (MPGN) in 1 KTR at an average time of 129.7 ± 33 days after COVID-19 infection (Table 2). After COVID-19 infection, the average times to develo-pment of noncollapsing FSGS, collapsing FSGS, and FSGS recurrence were 68 ± 31, 128.2 ± 43.8, and 88 ± 13 days, respectively. Nephrotic syndrome was noted in 66.7% of patients with noncollapsing FSGS and in all patients diagnosed with collapsing FSGS, FSGS recurrence, and MPGN. Hematuria was more pronounced clinically in all KTRs with IgA nephropathy, acute tubulointerstitial nephritis, and ATI diagnosis.

Among all patients, 47.1% of KTRs exhibited TMA in glomeruli, whereas 41.2% showed glomerular EC swelling, underscoring the extent of EC injury in glomeruli. Both patients with immune complex disease presented with TMA compared with 4 of 10 patients (40%) of KTRs with FSGS. Kidney transplant recipients with TMA experienced graft loss earlier (6.5 ± 1.7 mo) than those without TMA (10 ± 4.2 mo). Similarly, EC swelling in glomeruli was observed in both patients with immune complex disease and 5 of 10 KTRs (50%) of the FSGS group. However, no significant difference was shown in the average time of graft loss between KTRs with (7.5 ± 1.1 mo) and without (9 ± 4.3 mo) EC swelling (Table 2).

Notably, among 17 KTRs, 15 (88.2%) developed TCMR and/or ABMR, underscoring the intricate interplay between viral infection and graft rejection. Among 17 KTRs, 10 (58.8%) showed TCMR and 14 (82.4%) had ABMR at a mean time of 3.8 ± 1.3 months after COVID-19 infection. Ten KTRs (58.8%) had mixed rejection. Graft loss in KTRs with rejection was 46.7% (Table 3). The average time of graft loss was 6.2 ± 0.9 months for patients with rejection and 22 months for KTRs without rejection.

All KTRs were followed for an average of 16 ± 2.3 months after COVID-19, and 8 KTRs experienced graft loss at an average time of 8.2 ± 2 months. Kidney transplant recipients without graft loss, on the other hand, had an average graft survival time of 23.7 ± 1.9 months. As shown in Table 3, hospitalization of KTRs during COVID-19 was significantly associated with graft loss (P = .044). The presence of comorbidities such as hypertension and diabetes mellitus did not show significant differences between KTRs with and without graft loss (Table 3).

The incidence of graft loss was 60% and 66.7% for KTRs with collapsing and noncollapsing FSGS, respectively. The average time of graft loss after COVID-19 was 4.5 ± 1.5 months for noncollapsing FSGS and 7 ± 1.5 months for collapsing FSGS. Conversely, none of the KTRs with FSGS recurrence experienced graft loss during the follow-up. The remaining patients diagnosed with FSGS maintained functioning grafts throughout the follow-up period, which averaged 25.3 ± 5.4 months. Furthermore, KTRs diagnosed with acute tubulointerstitial nephritis showed a higher incidence of graft loss (66.7%) at an average time of 13.5 ± 8.5 months. Viral-inclusion-like nuclear changes in tubules significantly influenced graft survival (Table 3) (P = .044).

Discussion

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has affected global health and millions of people worldwide. Although COVID-19 primarily affects the respiratory system, emerging evidence indicates that COVID-19 can also affect other organs, including kidneys and renal allografts. This possibility poses additional challenge for KTRs who are already immunosuppressed, potentially leading to complications in their renal allografts.^6,7

The intensity of immunosuppression and specific medications used in KTRs can affect the severity of COVID-19 and allograft outcomes. Adjusting immunosuppressive regimens individually is crucial to balance the risk of allograft rejection and the severity of COVID-19.^15,16 In patients with severe COVID-19, temporary reduction or withdrawal of immunosuppressive medications may be necessary.

Most (64.7%) of our KTRs were on tacrolimus therapy; studies exploring whether tacrolimus increases the risk of COVID-19 infection have yielded mixed results. Some studies suggest that tacrolimus may not significantly affect susceptibility to the virus, whereas others have proposed a potential association.^16-19 Furthermore, the impact of tacrolimus on the severity of COVID-19 remains an ongoing area of research, with research suggesting that tacrolimus may reduce the risk of severe complications by decreasing the risk of cytokine storms and acute respiratory distress syndrome.¹⁶

Renal involvement in COVID-19 is common, with studies reporting varying prevalence rates. Renal manifestations include proteinuria, hematuria, and AKI, which are frequently observed in severe cases of COVID-19 and associated with worse clinical outcomes.^11,20-22 Acute kidney injury is a complex clinical syndrome characterized by ATI, which involves damage to renal tubular epithelial cells. The severity of ATI correlates with the degree of AKI.²³ Similarly, 35% of our KTRs developed AKI during COVID-19 infection, leading to renal allograft dysfunction. These patients required hemodialysis treatment and showed varied severity of allograft dysfunction. Biopsy findings were consistent with AKI, with widespread ATI observed in the tubules. Moreover, 66.7% of KTRs with AKI exhibited TMA features in renal allograft biopsies. The development of AKI was associated with increased disease severity, as evidenced by pneumonia, hospitalization, and the necessity of hemodialysis treatment.

The long-term effects of COVID-19 on renal allograft function are still under investigation. Most KTRs have been shown to recover renal function, but long-term follow-up is essential to assess the potential for late allograft dysfunction. In our study, we followed patients with AKI for 13.6 ± 4 months after COVID-19 infection. The renal function was recovered in AKI cases after renal replacement therapy except in 2 cases. These 2 patients experienced graft loss 3 and 5 months after COVID-19. In addition, 2 other KTRs developed different kidney pathologies, such as collapsing FSGS and acute tubulointerstitial nephritis, leading to graft loss at 6 and 22 months postinfection. The remaining 2 KTRs with AKI maintained functioning grafts during follow-up.

Even mild or asymptomatic COVID-19 has been shown to result in long-term renal consequences, such as persistent proteinuria, hematuria, and reduced glomerular filtration rate.^10,24-27 Prolonged follow-up is crucial to comprehend the extent of COVID-19-related renal dysfunction fully. In our study group, all KTRs were followed for an average of 16 ± 2.3 months after COVID-19, and all exhibited pathological kidney changes within an average of 129.7 ± 33 days.

Similarly to previously reported, new or increased proteinuria and hematuria were common findings among our KTRs with renal involvement.^10,24-27 Before diagnosis of COVID-19, only 41.2% of our KTRs had proteinuria, which escalated to the nephrotic range postinfection in 58.8% of cases and significant hematuria in 35.3%. Monitoring urinary parameters in COVID-19 patients can provide valuable insight into renal impairment and risk assessment. Kidney biopsies were performed on all our patients, revealing various glomerular lesions and damage indicative of the effect of COVID-19 on renal function.

Glomerular involvement in COVID-19 is often linked to EC injury, leading to EC swelling, fibrinoid necrosis, and TMA.^8-13,26 Similarly, our patients with glomerular involvement demonstrated significant EC injury, in which all patients with immune complex glomerulopathy had TMA and EC swelling in allograft biopsies. One patient with IgA nephropathy also had glomerular capillary fibrinoid necrosis. Nearly half of the KTRs diagnosed with FSGS also had TMA and EC swelling in allograft biopsies. This EC injury can be attributed to the widespread expression of ACE2 receptors in ECs, making them susceptible to SARS-CoV-2 infection.^8,11,26 Compared with KTRs without EC swelling and TMA, graft loss was earlier in patients with EC swelling and TMA. Kidney transplant recipients with EC swelling and TMA lost their graft 7.5 ± 1.1 and 6.5 ± 1.7 months after infection, respectively. Understanding these relationships has clinical implications, as the severity of glomerular involvement and associated EC injury can serve as prognostic markers for COVID-19 outcomes. Targeted therapies to preserve EC function and mitigate thrombotic complications may be beneficial in management of COVID-19-related renal complica-tions.

The presence of the virus in the kidneys and its interaction with renal cells have raised questions about the underlying mechanisms of renal involvement. Factors contributing to COVID-19-related AKI include hypovolemia, hemodynamic instability, systemic inflammation, cytokine release, increased vascular permeability, and direct viral infection of renal cells, including tubular epithelial cells and podocytes, through the ACE2 receptor.^{8,10,11,26,27-32} Viral entry into renal cells can induce cellular damage, inflammation, hypoxia, oxidative stress, and impaired mitochondrial function, ultimately leading to AKI.¹⁰ Obstructions in the renal tubules by inflammatory cells, cellular debris, and casts can further impair renal function.^10,11

In some COVID-19 cases, renal histopathological examination has revealed peculiar changes in the nuclei of tubular cells, resembling viral inclusion bodies seen in other viral infections.^11,30-32 Similarly, 47% of our KTRs showed intranuclear viral inclusion-like changes in tubular cells. These changes have sparked interest, and their nature and the effects in the context of SARS-CoV-2 infection remain areas of active research. Proposed mechanisms include viral replication as a result of direct viral infection, interferon-induced alterations in nuclear morphology, and the effect of proinflammatory cytokines.^23,30-32 Interferons, part of the antiviral immune response, may induce alterations in nuclear morphology as part of their antiviral activity.^23,31 Furthermore, severe cases of COVID-19 are associated with a cytokine storm characterized by excessive release of proinflammatory cytokines. These cytokines may directly or indirectly affect nuclear structures in renal cells.^30-32

Identification of inclusion-like changes in renal biopsies may serve as a histological marker of SARS-CoV-2 renal involvement and may indicate viral persistence and ongoing renal injury. Recognizing these changes may aid in risk stratification and prognostication for COVID-19 patients with renal involvement. Our results support this suggestion, with graft loss of 75% and 22.2% for cases with and without intranuclear-inclusion-like changes, respec-tively. In addition, the average time of graft loss was 5.6 ± 0.8 months for KTRs with inclusion-like changes, whereas time was 16 ± 6 months for patients without these intranuclear changes. Further research is needed to elucidate the precise mechanisms and clinical significance of viral inclusion-like changes in the nucleus of tubular cells in COVID-19 patients.

COVID-19-associated nephropathy (COVAN) refers to renal pathology and dysfunction directly related to SARS-CoV-2 infection, diagnosed through clinical and histopathological criteria. Specific histological features characterize COVAN, including podocyte injury, endothelial cell injury, and tubulointerstitial injury. Collapsing glomerulopathy is a severe form of glomerular involvement in COVAN, marked by glomerular collapse, podocyte hypertrophy, TMA, and severe proteinuria, especially at the nephrotic level.^12,13,26,33 Similarly, 100% and 40 % of our patients diagnosed with collapsing FSGS had shown nephrotic syndrome and TMA, respectively. The direct invasion of the virus is thought to trigger podocyte injury, leading to podocyte detachment, apoptosis, and disruption of the glomerular filtration barrier. The resultant podocyte damage contributes to glomerular collapse and proteinuria in collapsing FSGS. Furthermore, the excessive release of proinflammatory cytokines, such as interleukin 6 and tumor necrosis factor-α, may contribute to podocyte injury and glomerular collapse in patients with collapsing glomerulopathy.^{8,9,11,25,31,32} The prognosis of collapsing FSGS in COVID-19 is generally poor, with a high risk of progression to end-stage renal disease.^12,13,26,33 Our results confirm these findings, as 60% of our KTRs with collapsing FSGS lost their renal allograft at an average of 7 ± 1.5 months after COVID-19 infection. Moreover, de novo noncollapsing FSGS development was also associated with poor graft outcome, but KTRs with FSGS recurrence did not lose their graft during the follow-up period. Other glomerular lesions associated with COVAN include membranous glomerulonephritis, MPGN, minimal change disease, and IgA nephropathy.^8-11,24,32 Immune-mediated mechanisms and viral antigen-antibody interactions likely contribute to development of immune complex-mediated glomerulonephritis in COVID-19.

The COVID-19 pandemic has posed unique challenges for transplant recipients, as the virus can potentially dysregulate the immune system and trigger alloimmune responses, leading to an increased risk of allograft rejection.³⁴ Similarly, in our study, 88.2% of KTRs developed TCMR and/or ABMR, emphasizing the complex interplay between viral infection and graft rejection. The immune dysregulation in COVID-19 can prime T cells to recognize and attack the transplanted organ, potentially leading to an uptick in both TCMR and ABMR episodes.^{15,16,18,20-22,34} The mechanisms underlying these rejection episodes remain unclear and need further investigation. The increased rejection rates have raised concerns about graft survival and transplant success. Studies have shown a correlation between post-COVID-19 rejection episodes and accelerated graft loss.^15-20 Confirming this, the average time to graft loss was 6.2 ± 0.9 months for patients with rejection and 22 months for KTRs without rejection. This worrisome trend emphasizes the need for tailored immunosuppressive strategies, vigilant monitoring, and proactive mana-gement in KTRs with SARS-CoV-2 infection.

Conclusions

The effects of COVID-19 on renal health are multifaceted and extend beyond acute respiratory symptoms. As observed in COVAN, renal invol-vement can lead to acute and chronic kidney problems, glomerular damage, endothelial cell injury, and immune system dysregulation, particu-larly in transplant recipients. Tailored clinical management, vigilant renal function monitoring, and ongoing research into the interaction between SARS-CoV-2 and the kidneys are essential to addressing these challenges.

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