Patients who were admitted to the designated COVID wards in Cerrahpasa Medical Faculty, a tertiary healthcare center, between 15th March and 1st July 2020 were retrospectively analyzed. This period has been the first wave of the pandemic in our country and symptomatic patients were admitted immediately.
Hospitalized COVID-19 patients whose disease status was confirmed by a real-time polymerase chain reaction (RT-PCR) test for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2) were involved in the study. Kidney transplant patients and those who were younger than 18 years old were excluded from the study. As glomerular filtration rate (GFR) below 60 mL/min/1.73 m2 was already shown to be related to mortality , these patients were also excluded. (Figure-1).
Evaluation of COVID -19 patients
History, physical examinations, clinical features, laboratory tests, radiologic investigations, microbiological tests and in-hospital clinical progress of the patients were retrospectively investigated. The following data were used from each category:
-History: Age, co-morbidities (diabetes, hypertension, malignancy, ischemic heart disease/heart failure), use of drugs or contrast agents.
-Physical examination: State of consciousness, blood pressure, volume status
-Laboratory tests: Urine analysis, complete blood count (CBC), serum urea, serum creatinine, urea-to-creatinine ratio, baseline GFR, uric acid, electrolytes (sodium, potassium, chloride, phosphorus, calcium, magnesium), albumin, transaminases, blood gas analysis (pH, pO2, pCO2, HCO3), CRP, pro-calcitonin, D-dimer, ferritin, lactate dehydrogenase (LDH), creatine kinase (CK), oxygen saturation.
-Radiologic Investigations: Chest computed tomography (CT), renal ultrasonography, abdominal CT (when needed).
-Microbiological tests: Blood culture and urine culture studies (when needed)
-Clinical progress: Antimicrobial treatment, anti-inflammatory treatment, the day of AKI, criteria to diagnose AKI, AKI stage, AKI duration, COVID-19 severity, duration of hospital stay, admission to ICU, renal replacement therapy (RRT) requirement and type, in-hospital mortality.
To define AKI, Kidney Disease Improving Global Outcomes (KDIGO) criteria were used; an absolute increase of 0.3 mg/dl in creatinine levels in 48 hours or 50% increase in creatinine levels in the last 7 days or when urine output is less than 0.5 mL/kg/h for the previous 6 hours. .
We observed the progression of creatinine values in all patients who were admitted with COVID-19 diagnosis. In patients with an increase in creatinine levels, we directly applied KDIGO criteria. The first calculated creatinine level after being admitted to hospital was taken as the baseline creatinine level for these patients. For patients with a decrease in their creatinine levels following hospital admission, KDIGO criteria were applied according to patients’ previous creatinine levels. When there was no previous data 7 to 365 days prior to hospital admission, baseline creatinine levels were backwards calculated using the MDRD75 formula [5,6].
Stage of the AKI was also defined according to KDIGO criteria; 1.5 – 1.9 times baseline creatinine or 0.3 mg/dl absolute increase as stage 1 AKI; 2.0 – 2.9 times baseline creatinine as stage 2 AKI and more than 3.0 times baseline creatinine or increase to more than 4.0 mg/dL as stage 3 AKI.
Estimated glomerular filtration rate (eGFR) was used to define the kidney functions and it was calculated by Chronic Kidney Diseases Epidemiology Collaboration (CKD-EPI) formula.
State of consciousness was evaluated by Glasgow Coma Scale and a drop of more than 2 points was a reason to call intensive care unit (ICU) team to evaluate the patient for a possible ICU admission. Mean arterial pressure was calculated as: [(systolic blood pressure) + (2 x diastolic blood pressure) / 3].
Hematuria was defined as the presence of more than three red blood cells per high power field in the urine sediment. Proteinuria was detected semi-quantitavely by a fully automated urine dipstick test. The level of proteinuria was graded as +1, +2 or +3; indicating levels between 30-100 mg/dL, between 100-300 mg/dL and over 300 mg/dL respectively.
Hyponatremia (<135 mmol/L), hypernatremia (>145 mmol/L), hypochloremia (<98 mmol/L), hyperchloremia (>107 mmol/L), hypokalemia (<3.5 mmol/L), hyperkalamia (5.1 mmol/L), hypocalcemia (<8.4 mg/dL), hypercalcemia (>10.2 mg/dL), hypophosphatemia (<2.5 mg/dL), hyperphosphatemia (>4.5 mg/dL), hypomagnesemia (<1.6 mg/dL), hypermagnesemia (2.6 mg/dL), acidosis (pH<7.35) and alkalosis (pH>7.45) were all described according to the reference range of respective laboratory measurements. Calcium levels were corrected according to serum albumin levels.
We defined three groups on the basis of the timing of AKI; those seen on admission, those developed in the 1st week and those developed after the 1st week.
Etiologic evaluation of AKI were carried out according to following criteria:
- Transient pre-renal AKI was defined when creatinine levels could be reversed to baseline levels with relevant fluid resuscitation in 24 to 72 hours.
- AKI was attributed to rhabdomyolysis in patients with at least five times elevated CK (i.e, >950 U/L) above upper normal limit with concomitant increase in LDH and transaminases.
- Hypoxemia related kidney damage was noted in patients who had disrupted gas exchange. Such disruption was documented with partial oxygen pressure lower than 60 mmHg despite the use of high flow oxygen therapy or mechanical ventilation (either non-invasive or invasive) or when respiratory acidosis developed with increasing levels of CO2 retention.
- Inflammation mediated AKI is considered in patients who have increasing levels of ferritin reaching to 5 times above the normal upper level (>750 ng/mL) or increasing levels of D-dimer that reached at least ten times of the upper normal limit (>5 mg/L).
- Secondary bacterial infections were diagnosed by blood cultures or urine cultures.
- AKI was attributed to drug toxicity if AKI developed after the patient was exposed to nephrotoxic drugs or agents.
Inflammation mediated injury assumption
It’s known from before that immune system dysregulation, complement system activation and hyper-coagulopathy were all linked with each other . We have observed a similar phenomenon in our etiologic analysis. It may not be always possible to define which has started before and caused the others. That is why, AKIs in patients either with increasing D-dimer levels or cytokine release syndrome that manifests with increasing levels of ferritin were associated with the hyper-inflammation state of COVID-19 .
Severity of COVID-19
Clinical picture of COVID-19 patients were classified according to a scale that included following categories:
- Mild (symptoms of upper respiratory tract infection or digestive symptoms)
- Moderate (pneumonia without hypoxemia)
- Severe (pneumonia with hypoxemia)
- Critical (acute respiratory distress syndrome, shock) .
Patients were admitted to intensive care unit, if arterial partial oxygen pressure was persistently below 50 mmHg despite the use of venturi mask, when there was accumulation of CO2 rising above 55 mmHg, when the patient had loss of consciousness or when the patient was consistently hypotensive despite fluid resuscitation.
Acquisition of Data
Hospital electronic health records and patient files were used to collect the data. Admission day to the COVID ward was accepted as the day zero of the patient follow-up.
Data were expressed as means ± standard deviation. Continuous variables were compared by independent samples t-test. Categorical variables were compared either by Pearson chi-square or Fisher’s exact test. For the comparison of three groups that were created according to the timing of AKI, ANOVA test was performed. Tukey HSD test was used for post-hoc analysis. All tests were applied using SPSS for Windows, version 22.0 software (SPSS Inc. Chicago, IL, USA). P values less than 0.05 were accepted as statistically significant.