The study enrolled patients with CKD stages 3–5 (GFR < 60 mL/min/1.73m2); those with CKD stages 1 or 2 were not included because of their frequently fluctuating GFR values. Moreover, patients with end-stage renal disease undergoing dialysis treatment were excluded from the study due to sustained low GFR values. In this study, we selected eGFR over serum creatinine as an indicator of renal function because eGFR changes linearly in the natural course,9,10 whereas serum creatinine does not.11 The serum creatinine data during routine outpatient visits were collected and used to calculate eGFR. However, creatinine levels measured during hospitalization, in the emergency room, during infections, while taking analgesics, or after surgery or an invasive procedure were not included in the analysis.
Urine protein is another effective indicator of nephropathy or kidney damage. However, in patients with diabetes, microalbuminuria is the most accurate indicator or early detector of nephropathy,12 whereas the protein-to-creatinine ratio in spot morning urine specimens is a precise and reliable indicator of disease progression and mortality risk13 in those without diabetes but with chronic nephropathy.14,15 In our study, UPCR was used as the sole indicator both in those with and without diabetes. Moreover, the case reports of MCD following COVID-19 vaccination support this approach. Our study suggested that proteinuria caused by de novo MCD or an aggravation of pre-existing proteinuria could be related to nephropathy progression.
When we calculated eGFR changes, changes in eGFR were first calculated as a difference in GFR per month and then converted to a difference per year. The eGFR changes during the control periods were calculated in the same manner. By using a difference-in-differences study design to compare eGFR and UPCR changes after vaccination with the previous year, the impact of COVID-19 vaccination on renal function was examined. However, the change in renal function could be affected by numerous confounding factors, including age, sex, comorbidities such as diabetes or hypertension, and medication use. We thus performed a paired-sample t test to avoid bias as much as possible.
Our results indicated that most patients with CKD in Taiwan received the Oxford-AstraZeneca and Moderna vaccines due to policy considerations and the timing of vaccine authorization approval and import. As a result of Taiwan’s vaccine distribution policy, the Pfizer BNT vaccine was initially reserved for younger populations. Therefore, because those with CKD tend to be older, only a small percentage of the patients considered in this study received the Pfizer BNT vaccine.
Studies have revealed that both messenger RNA (e.g., Pfizer BNT) and adenoviral vector (e.g., Oxford-AstraZeneca) vaccines could cause MCD-associated symptoms such as nephrotic syndrome and AKI. Such evidence also suggests that podocyte injury caused by vaccine-induced T cell responses could be the primary cause of these symptoms.6,7,8 Our analysis revealed no difference in the impact on renal function between different types of vaccines, including mRNA, adenoviral vector, and protein subunit vaccines. As such, our findings suggest that vaccines are not the major cause of elevated proteinuria and GFR changes. The possible mechanism affecting renal function may involve a T-cell-mediated immune response process.
Furthermore, the elevation in proteinuria observed in our study was also noted in the reported cases of MCD with nephrotic syndrome. However, in our study the eGFR did not change consistently with the AKI which occurred in the reported cases of MCD; by contrast, the eGFR unexpectedly increased after vaccination. Beyond that, the rise in GFR along with the increase in proteinuria was similar to glomerular hyperfiltration in the early stages of diabetic nephropathy. However, whether GFR will remain the same, return to normal, or even worsen after the glomerular hyperfiltration phase remains unknown. Because the COVID-19 pandemic has not yet subsided, booster vaccination (third dose of vaccine) has been widely implemented worldwide to prevent the spread of SARS-CoV-2; some countries have even begun to administer fourth shots. The present findings may be used as a reference for physicians who are concerned about vaccination safety in patients with CKD.
Limitations
This was a retrospective and observational study, and a matched pairs design with no control cohort was employed. All participants were from one regional hospital.