Clinical Characteristics of Hospitalized Patients with 2019 Novel Coronavirus Disease Indicate Potential Proximal Tubular Dysfunction
The 2019 novel coronavirus disease (COVID-19), caused by the 2019 novel coronavirus (2019-nCoV), emerged in Wuhan, China, in December 2019. This highly infectious disease primarily manifests as pneumonia but has also been associated with systemic injuries, including renal dysfunction. The angiotensin-converting enzyme 2 (ACE2) serves as the cell entry receptor for 2019-nCoV, and its expression is notably dominant in the proximal tubules of the kidney. This study aimed to retrospectively analyze clinical data from hospitalized COVID-19 patients to identify evidence of proximal tubule injury.
The study was conducted at the Sino-French branch of Tongji Hospital in Wuhan, China, from January 28, 2020, to February 10, 2020. Patients were diagnosed and classified according to the “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 4).” Those with a history of chronic kidney disease (CKD) or abnormal urinalysis results in the past three months before admission were excluded. The study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Tongji Hospital.
Clinical electronic medical records, nursing records, and laboratory findings were reviewed for all patients. Data collected included age, sex, history of chronic diseases, days from symptom onset to hospital admission, and laboratory values at admission. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Hematuria and proteinuria were defined as more than 1+ hemoglobin or protein in urine dipstick tests. CKD was diagnosed according to the Kidney Disease: Improving Global Outcomes criteria.
Statistical analyses were performed using SPSS 21.0. Categorical variables were presented as counts and percentages, and continuous variables were expressed as median and interquartile range (IQR) or mean ± standard deviation, depending on the distribution of normality. The Student’s t-test or the Wilcoxon rank-sum test was used for continuous variables, while the Chi-squared test or the Fisher exact test was used for categorical variables. A two-sided P < 0.05 was considered statistically significant.
A total of 93 COVID-19 patients were enrolled, including 22 (23.7%) common and 71 (76.3%) severe cases. The median age was 60 years (IQR, 46–68 years; range, 20–88 years), with 45 (48.4%) patients older than 60 years. The median duration from symptom onset to hospital admission was 9.0 days (IQR, 6.0–11.0 days). Among the patients, 46 (49.5%) had one or more coexisting medical conditions, with hypertension (34 [36.6%]), diabetes (13 [14.0%]), cardiovascular disease (4 [4.3%]), chronic respiratory disease (2 [2.2%]), and malignancy (1 [1.1%]) being the most common. Three (3.2%) patients presented with vomiting, and five (5.4%) had diarrhea.
Clinical data were analyzed according to sex. Male patients (n = 41) exhibited significantly lower serum sodium levels (136.8 ± 3.7 mmol/L vs. 139.0 ± 2.9 mmol/L; t = 3.191, P = 0.002) and eGFR (86.7 ± 20.6 mL·min⁻¹·1.73 m⁻² vs. 96.8 ± 19.7 mL·min⁻¹·1.73 m⁻², t = 2.384, P = 0.019) compared to female patients (n = 52). Male patients also had higher serum potassium (4.3 ± 0.5 mmol/L vs. 4.1 ± 0.4 mmol/L, t = -2.044, P = 0.044) and high-sensitivity C-reactive protein (hs-CRP) levels (46.0 [23.8, 140.0] mg/L vs. 34.9 [8.5, 60.0] mg/L; Z = -2.364, P = 0.018). Hyponatremia was observed in 24 (25.8%) patients at admission, with a higher incidence in men (16 [39.0%]) than in women (8 [15.4%]) (χ² = 6.691, P = 0.010). Hypochloridemia was present in 32 (34.4%) patients, with a significant sex-related difference (male vs. female: 53.7% vs. 19.2%, χ² = 12.039, P = 0.001). Hypouricemia was observed in 19 (20.4%) patients, with no significant sex-related difference (male vs. female: 26.8% vs. 15.4%, χ² = 1.847, P = 0.174).
Urinalysis results were available for 79 patients, revealing proteinuria in 27 (34.2%) and hematuria in 16 (20.3%). All cases of proteinuria were mild (+ to ++), with 25 occurring in severe cases and two in common cases. The proportion of severe cases was significantly higher in patients with proteinuria than in those without (92.6% vs. 3.8%, χ² = 6.958, P = 0.008). Patients with proteinuria had significantly lower serum sodium levels (136.8 ± 3.7 mmol/L vs. 139.0 ± 3.0 mmol/L, t = 2.793, P = 0.007) and a higher incidence of hematuria (37.0% vs. 11.5%, χ² = 7.154, P = 0.007). Increased serum urea (5.1 [3.5, 6.6] mmol/L vs. 3.5 [2.9, 4.4] mmol/L; Z = 3.046, P = 0.002) and uric acid levels (266.1 ± 109.8 mmol/L vs. 216.9 ± 88.0 mmol/L; t = -2.056, P = 0.046) and decreased eGFR (87.9 ± 22.7 mL·min⁻¹·1.73 m⁻² vs. 97.4 ± 17.7 mL·min⁻¹·1.73 m⁻²; t = 2.057, P = 0.043) were also observed in patients with proteinuria.
Glucosuria was found in 11 (13.9%) patients, with a median age of 64 years (range: 50–84 years). Three patients had diabetes, and none had a history of CKD or genetic tubular disorders. At admission, random blood glucose levels were above the normal range (4.11–6.05 mmol/L) in five patients, including three with diabetes. Fasting blood glucose (FBG) levels were abnormal in three diabetic patients the following day, while the other two patients returned to normal levels (4.86 and 4.57 mmol/L, respectively). Eight patients (10.1%) presented with renal glucosuria, five of whom had both proteinuria and hematuria, and one had only proteinuria.
Renal involvement has been evident in coronavirus-related diseases, including severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID-19. Abnormal urinalysis results and renal function impairment are common in COVID-19, likely due to the abundance of ACE2 in the kidney. This study found significantly lower eGFR and serum sodium levels and higher hs-CRP levels in male patients, consistent with reports suggesting that male patients have a predisposition toward COVID-19 and poorer prognosis. Whether male patients have poor renal prognosis requires further investigation.
Hyponatremia was observed in 25.8% of patients, similar to findings in severe acute respiratory syndrome (29% to 60%). The underlying mechanism remains unclear, but vomiting and diarrhea, which can induce hypovolemic hyponatremia, were present in only 3.2% and 5.4% of patients, respectively. Systemic inflammation, a central factor in pneumonia, may also contribute to hyponatremia. Proximal tubule injury could disrupt sodium and electrolyte transport, but this requires further investigation.
Glucosuria was found in eight non-diabetic patients, all with FBG within the normal range. Two patients had slightly increased random blood glucose levels but below the renal threshold for glucose (10 mmol/L), suggesting proximal tubule injury as the cause of renal glucosuria.
Proximal tubule injuries can manifest as tubular proteinuria, renal glucosuria, renal hypouricemia, and electrolyte and acid-base balance disorders. This study found renal glucosuria in 10.1% of patients, mild proteinuria in 34.2%, hyponatremia in 25.8%, and hypouricemia in 20.4%. No patient had nephrotic-range proteinuria, but 27 had mild proteinuria (+ to ++). Patients with proteinuria were more severe, indicating its potential as a marker for disease severity. However, urine protein electrophoresis and quantification were not performed, and urinary markers for tubular injuries, such as neutrophil gelatinase-associated lipocalin, were not measured. Transient proteinuria due to fever and systemic inflammation could not be ruled out. These findings suggest potential proximal tubule dysfunction in COVID-19 patients.
This study had limitations, including its retrospective design, which precluded important examinations for solid evidence of renal tubular injury. Clinicians should prioritize workups for tubular injury, especially during the COVID-19 pandemic. The study’s selection bias, with most patients being severe cases, limits generalizability. Further studies with larger sample sizes are needed to confirm sex-related differences in the general patient population.
In conclusion, this study found that male COVID-19 patients had lower eGFR and a higher incidence of hyponatremia compared to female patients. The presence of renal glucosuria, mild proteinuria, and hyponatremia in COVID-19 patients indicates potential proximal tubular injury, highlighting the need for further investigation.
doi.org/10.1097/CM9.0000000000000945
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