Association between COVID-19 and the development of chronic kidney disease in patients without initial acute kidney injury

Table of Contents

Patient selection

Of the 156,386,048 patients in 133 TriNetX healthcare organizations, 34,764,412 patients aged ≥ 18 years visited healthcare facilities at least twice between 2022 and 2023 (Fig. 1). Among them, 1,451,073 were diagnosed with first-time COVID-19 and 666,902 with first-time influenza. After applying the exclusion criteria (Supplemental Table 1), 636,264 COVID-19 patients and 141,737 patients with influenza remained eligible. Propensity score matching 1:1 by age, sex, race, and comorbidities yielded final analytical cohorts of 141,587 patients in each group.

Patient characteristics before and after matching

Prior to propensity score matching, our study included 636,264 patients in the COVID-19 group and 141,737 patients in the influenza group, respectively. Several notable differences in the baseline characteristics were observed between the groups (Table 1). The COVID-19 group was slightly older (mean age 46.9 ± 17.6 years vs. 42.6 ± 16.3 years) and had a marginally higher body mass index (29.8 ± 7.5 vs. 29.0 ± 7.2). While gender distribution was similar between groups (56.4% vs. 56.6% female), racial composition showed more variation, with the COVID-19 group having a higher proportion of White patients (57.7% vs. 49.6%) and Black or African American patients (14.2% vs. 9.9%), but a lower proportion of patients of unknown race (16.0% vs. 27.1%).

Table 1 Patient characteristics before and after matching.

After 1:1 propensity score matching, we achieved well-balanced cohorts of 141,587 patients in each group, with standardized differences less than 0.1 for all baseline characteristics (Table 1). The matched cohorts had comparable demographic characteristics, including age (42.5 ± 16.5 vs. 42.6 ± 16.3 years), body mass index (28.7 ± 7.2 vs. 29.0 ± 7.2), gender distribution (56.7% vs. 56.6% female), and racial composition. Comorbidity profiles were also well-balanced between the matched groups, with similar prevalences of essential hypertension (13.2% vs. 13.4%), neoplasms (8.6% vs. 8.9%), and other chronic conditions. Laboratory values, including hemoglobin (13.6 ± 1.9 vs. 13.7 ± 1.8 g/dL), albumin (4.2 ± 0.6 vs. 4.2 ± 0.4 g/dL), and hemoglobin A1c (5.9 ± 1.4% vs. 6.0 ± 1.8%), showed no significant differences between the matched groups.

Outcome at 6-month and 12-month follow-up

During the first 6 months of follow-up, patients in the COVID-19 group demonstrated significantly higher rates of renal dysfunction than those in the influenza group (Table 2). The incidence of AKI was threefold higher in COVID-19 patients (0.25% vs. 0.08%, HR 3.16, 95% CI 2.57–3.88, P < 0.0001), whereas advanced CKD occurred more than twice as frequently (0.14% vs. 0.07%, HR 2.25, 95% CI 1.76–2.87, P < 0.0001). Similarly, reduced eGFR (< 60 mL/min/1.73 m²) was substantially more common in the COVID-19 group (0.68% vs. 0.22%, HR 3.32, 95% CI 2.92–3.78, P < 0.0001). The disparity in renal dysfunction persisted through 12 months of follow-up (Table 2). Kaplan-Meier curves show the cumulative incidence of renal dysfunction in COVID-19 versus influenza patients (Fig. 2). The COVID-19 group maintained higher rates of AKI (0.45% vs. 0.15%, HR 3.04, 95% CI 2.61–3.55) (Fig. 2a), advanced CKD (0.25% vs. 0.13%, HR 2.02, 95% CI 1.69–2.42) (Fig. 2b), and reduced eGFR (1.23% vs. 0.43%, HR 3.01, 95% CI 2.74–3.30) (Fig. 2c). All differences at 12 months remained statistically significant (P < 0.0001), indicating a consistently elevated risk of renal dysfunction in COVID-19 patients compared with those with influenza.

Table 2 New-onset renal dysfunction during 12-m follow-up after covid-19 or influenza infection.

Subgroup analysis of gender on clinical outcomes

In a subgroup analysis stratified by sex, both females (n = 80,632 per cohort) and males (n = 56,745 per cohort) showed significantly higher incidence rates of AKI, advanced CKD, and reduced eGFR in the COVID-19 group than in the influenza group during the 12-month follow-up period (all p < 0.0001) (Table 3). However, the HR for AKI and reduced eGFR were notably higher in males than in females. For AKI, the HR was 3.78 (95% CI 3.04–4.71) in males compared to 2.27 (95% CI 1.79–2.86) in females. Similarly, for reduced eGFR, the HR was 3.13 (95% CI 2.71–3.62) in males versus 2.84 (95% CI 2.52–3.19) in females. These findings suggest that while COVID-19 infection poses a significantly higher risk of developing renal dysfunction than influenza infection in both sexes, males may be more susceptible to AKI and reduced eGFR than females after COVID-19 infection.

Table 3 Subgroup analysis of gender on new-onset renal dysfunction during 12-month follow-up.

Subgroup analysis of age on kidney dysfunction

Analysis of age-stratified outcomes at 12 months revealed distinct patterns of renal dysfunction between younger (18–45 years) and older (> 45 years) patients (Table 4). In the younger cohort of 67,859 patients per group, COVID-19 patients demonstrated a significantly higher risk of AKI (0.16% vs. 0.07%, HR 2.29, 95% CI 1.62–3.24, P < 0.0001) and reduced eGFR (0.23% vs. 0.05%, HR 4.47, 95% CI 3.09–6.49, P < 0.0001) than influenza patients. However, the difference in the incidence of advanced CKD was not statistically significant in this age group (0.03% vs. 0.02%, HR 1.53, 95% CI 0.76–3.07, P = 0.2311).

Table 4 Subgroup analysis of age on renal dysfunction during 12-month follow-up.

The older cohort (56, 782 patients per group) showed more pronounced differences in all kidney outcomes. COVID-19 patients over 45 years of age exhibited substantially higher rates of AKI (0.87% vs. 0.28%, HR 3.46, 95% CI 2.89–4.14, P < 0.0001), advanced CKD (0.56% vs. 0.29%, HR 2.09, 95% CI 1.74–2.53, P < 0.0001), and reduced eGFR (2.79% vs. 1.00%, HR 3.08, 95% CI 2.80–3.40, P < 0.0001) than their influenza counterparts. These findings suggest that older age may be an important risk modifier of renal dysfunction following COVID-19.

Sensitivity analysis

In sensitivity analyses (Supplemental Table 2), we first incorporated baseline eGFR as a matching variable, achieving well-balanced cohorts (COVID-19:96.9 ± 21.6 mL/min/1.73 m²; Influenza: 97.2 ± 19.9 mL/min/1.73 m², standardized difference: 0.0341). Despite this balance, COVID-19 patients continued to exhibit significantly higher 12-month risks for AKI (HR 2.80, 95% CI 2.44–3.21), advanced CKD (HR 2.38, 95% CI 2.04–2.77), and eGFR < 60 mL/min/1.73 m² (HR 2.78, 95% CI 2.56–3.02) (all P < 0.0001).

After excluding patients who developed AKI within one year post-infection, COVID-19 patients remained at elevated risk for advanced CKD (HR 1.88, 95% CI 1.59–2.22, P < 0.0001) and eGFR < 60 mL/min/1.73 m² (HR 2.62, 95% CI 2.40–2.85, P < 0.0001), suggesting that COVID-19 may contribute to chronic kidney dysfunction independent of AKI (Supplemental Table 2).

When including patients with initial severe disease (defined as AKI, ICU admission, rhabdomyolysis, or sepsis within one month of infection), COVID-19 patients consistently demonstrated higher risks for AKI (HR 2.27, 95% CI 2.03–2.54), advanced CKD (HR 1.68, 95% CI 1.48–1.91), and eGFR < 60 mL/min/1.73 m² (HR 2.74, 95% CI 2.53–2.96) (all P < 0.0001) (Supplemental Table 2).

Finally, in a matched comparison of COVID-19 patients with and without early hospitalization, those who were hospitalized had higher risks for AKI (HR 2.43, 95% CI 2.14–2.76, P < 0.0001) and eGFR < 60 mL/min/1.73 m² (HR 1.56, 95% CI 1.43–1.69, P < 0.0001). However, there was no significant difference in the risk of advanced CKD (HR 1.05, 95% CI 0.89–1.24, P = 0.591), suggesting that while early hospitalization may help identify patients at higher risk for acute complications and reduced eGFR, it does not necessarily translate into an increased risk of advanced CKD (Supplemental Table 2).

Cox proportional hazards analysis

Cox proportional hazards analysis revealed several significant risk factors for new-onset advanced CKD (Fig. 3). Demographic factors, including age at index (HR 1.07, 95% CI 1.07–1.08) and male sex (HR 1.18, 95% CI 1.10–1.26) showed mild but significant associations. Diabetes mellitus (HR 2.42, 95% CI 2.24–2.62) and essential hypertension (HR 2.14, 95% CI 1.97–2.33) emerged as the strongest clinical predictors. Several comorbidities also showed significant associations, including malnutrition (HR 1.77, 95% CI 1.43–2.18), obesity (HR 1.28, 95% CI 1.17–1.40), neoplasms (HR 1.18, 95% CI 1.09–1.27), depressive episodes (HR 1.16, 95% CI 1.05–1.29), and ischemic heart diseases (HR 1.10, 95% CI 1.00-1.21). Notably, nicotine dependence, alcohol-related disorders, cerebrovascular diseases, liver diseases, atrial fibrillation, and COVID-19 vaccination status were not significantly associated with kidney dysfunction (all P > 0.05). The analysis also confirmed an elevated risk in the COVID-19 cohort compared to the influenza cohort (HR 2.29, 95% CI 1.97–2.67, P < 0.0001).