A total of 1056 patients were admitted in this specified period. The mean age of COVID-19 patients in our hospital cohort was 55 ± 15 years old, 582 (55,2%) of them were males while 474 (44,8%) of them were females.
427 patients were confirmed by RT-PCR. Mortality of admitted COVID-19 patients in with a confirmed RT-PCR was previously found to be 12% in our center . 104 of them experienced AKI (24,3%). There were 44 patients who had eGFR under 60 ml/min/1.73 m2. While15 of them had AKI (34%), 8 of them died (53,3%).
As can be seen in figure-1, 89 patients who developed AKI with an eGFR of over 60 ml/min/1.73 m2 were included in the final analysis. Patients who were included in our study were older than other patients in the general COVID-19 cohort (62,4 ± 14,2 years) and there was a male predominance (67 males, 75%).
Twenty-nine (32%) of the patients had AKI on admission. 33 of them (37%) developed AKI during the first week of admission and 27 patients (30%) developed AKI starting from the second week of admission. For patients who developed AKI later than hospital admission date, AKI developed on 6,7 ± 5,4 days.
Initial laboratory values on hospital admission day were shown in table-1 and in-hospital prognostic indices of all 89 patients who were included in the study can be found in table-2.
Patients who had AKI on admission
Twenty-nine patients had AKI on admission.
- Kidney functions in the 12 (41,3%) of on-admission AKIs were rescued by fluid resuscitation and were accepted to have transient pre-renal AKI due to hypovolemia.
- Two (6,8%) of the patients had high creatine kinase (CK) levels with concomitant high LDH and transaminase levels and accepted to have rhabdomyolysis related AKI. Both of these patients also had increasing levels of either ferritin (>750 ng/mL) or D-dimer (>5 mg/L).
- Six patients (20,6%) had documented gas exchange disruptions (persistent hypoxemia or hypercapnia). These patients were considered to have hypoxemic kidney injury. 4 of these patients also had high levels of ferritin (>750 ng/mL) or D-dimer (>5 mg/L) levels.
- A total of eight patients (27,5%) who had hyperferritinemia and/or high D-dimer levels without rhabdomyolysis. Thus, they were noted to have hyper-inflammation related AKI.
-Direct SARS-CoV-2 renal involvement was suspected only in a one 77 years old male patient (3,4%) who had shown new developed proteinuria concomitant with AKI despite normal levels of CK levels or inflammatory and coagulation markers.
COVID severity of the patients with AKI on admission was mainly moderate and just 7 of them (24%) had severe or critical disease.
Patients who had AKI in the 1st week.
Thirty-three patients experienced AKI during the 1st week.
- 10 (30,3%) patients had transient pre-renal AKI which was cured by relevant fluid therapy.
- Rhabdomyolysis was noted in four patients (12,1%) who had high creatine kinase (CK) levels with concomitant high LDH and transaminase levels. All of these four patients also had concomitant hyperferritinemia (>750 ng/mL).
- A total of 13 patients (39,3%) had high ferritin or D-dimer levels without rhabdamyolysis and accepted to have hyper-inflammation mediated kidney injury.
- Three patients (9%) either had hypoxemia or increasing levels of CO2 retention. These were accepted to have hypoxemia related AKI.
- AKI in three patients (9%) of this group was thought to be related to drug toxicity (contrast agents in two patients and non-steroid anti-inflammatory drug in one patient).
When COVID severity of the patients was evaluated, 14 of these 33 patients (42%) were classified as severe or critical.
Patients who had AKI after 1st week:
Twenty-seven patients had AKI after the 1st week of their admission.
- AKI in one patient (3,7%) could be cured by relevant fluid therapy and accepted to have transient pre-renal AKI.
- Six patients had very high levels of CK (22,2%) with concomitant high LDH and transaminase levels and noted to have rhabdomyolysis. All of these patients also had either high D-dimer or ferritin levels.
- Two patients (7,4%) had severely disrupted gas exchange without concomitant high ferritin or D-dimer levels. AKI in these patients were attributed to hypoxemia.
- Sixteen patients (59,2%) had very high levels of either ferritin (>750 ng/mL) or D-dimer (>5 mg/L). These patients were accepted as hyper-inflammation induced AKI.
- Two patients (7,4%) had contrast agent induced AKI.
Clinical evaluation pointed out to severe or critical illness in 22 of these 27 patients (81%).
Urine analysis was available in a total of 35 patients. Hematuria was the most prominent finding, which was seen in 21 of them. Proteinuria was documented in 9 patients and they were all 1+ semiquantitavely. Proteinuria was going along with hematuria in 7 patients while two patients had isolated proteinuria.
Chest CT to investigate pulmonary involvement was performed in all patients. COVID pneumonia was detected in a total of 82 patients (92,1%). (28 of the on admission AKIs, 29 of the 1st week AKIs and 25 of the AKIs after 1st week).
Kidney imaging (urinary ultrasonography or abdominal CT) was available in a total of 14 patients. Eight of them were reported to be completely normal. Three patients had one sided nephro-urolithiasis, one patient had one sided pelvic ectasia, one had prostatic hypertrophy and one had the findings of cystic kidney diseases. None of the imaging studies yielded obstruction findings. Pathologies revealed by imaging studies could explain hematuria in some patients but none could be attributed to their AKIs.
Electrolyte and acid/base disturbances
Hypochloremia and hyponatremia were the most common electrolyte abnormalities in our cohort with 65 of the 89 patients (73%) experiencing hypochloremia and 50 (56,1%) of the patients having hyponatremia. Hypernatremia and hyperchloremia was seen in 22 (24,7%) and 18 (20,2%) of the patients respectively. Among potassium abnormalities, hyperkalemia developed in 35 (39,3%) of the patients, while hypokalemia was seen in 16 (17,9%) of them. Calcium disturbances was seen less frequent, hypocalcemia in 16 patients (17,9%) and hypercalcemia just in 3 patients (3,3%). Among patients for whom phosphorus levels were evaluated (79 patients); 22 had hypophosphatemia (27,8%) and 20 patients (25,3) had hyperphosphatemia. In patients who had their magnesium levels checked (83 patients) 6 (6,7%) had hypomagnesemia and 21(25,3%) had hypermagnesemia.
Acidosis (respiratory and/or metabolic) developed in 23 (25,8%) of the patients and respiratory alkalosis was seen in 38 (42,6%) of them.
Although there is no specific validated treatment for COVID-19 yet, some antiviral therapies were applied depending on the institutional availabilities and in accordance with the ministry of health (MoH) treatment guidelines. These include different combinations of hydroxychloroquine, favipiravir and lopinavir. Anti IL-6 receptor antibody tocilizumab or steroids were used in patients who had high inflammatory response. Low-molecular-weight heparin were prescribed for all patients in line with the MoH guidelines . These can be found in supplementary document-2. Continuous renal replacement therapy (CRRT) in ICU setting was performed with Prismaflex® system in a citrate anti-coagulated circuit, aiming a blood flow of around 20 mL/kg/hour.
Comparison between the groups denoted by the timing of AKI
Patients of the three groups (on admission AKI, 1st week AKI, after the 1st week AKI) were in similar age and had similar baseline mean arterial pressure, creatinine and hemoglobin levels. Co-morbidities such as diabetes, hypertension, malignancies and ischemic heart diseases/heart failure were also similar between three groups. While CRP and D-dimer levels on admission didn’t differ between the groups, patients who were presented with lower lymphocyte counts tend to develop AKI later in the disease course. Patients who had AKI on admission day had higher initial uric acid levels. All initial laboratory values of the patients can be found in table-3.
In hospital stay length, intensive care unit (ICU) requirement and mortality was higher when AKI developed later in the disease course, especially after 7th day. Patients who develop later AKIs had lower serum albumin levels as well as lower arterial O2 pressure and oxygen saturation levels. Pre-dominant stage of AKI was stage 1; however, stage 2 & 3 AKIs, which have worse prognosis tend to increase with AKIs that occurred later (table-4). AKI related prognostic indices of patients can also be found in table-4.
While there were no significant differences between the initial values of the three groups, comparison of changes in the inflammatory markers put forth significant differences. Nadir lymphocyte counts were significantly lower while peak CRP and peak D-dimer levels were significantly higher for patients who developed AKI later in the disease course (Table-5). Although it couldn’t reach the statistical significance, peak ferritin levels were also higher for patients who developed AKI later.
Sodium, chlorine and potassium abnormalities were more common in patients who developed AKI later. These included both abnormally low and abnormally high levels of sodium, chlorine and potassium (Table-5). Among absolute electrolyte levels on the day of AKI, sodium levels tend to be higher in patients who developed AKI later (Table-3).
Treatment modalities were not different between the groups (Table-6). CRRT had to be performed in 6 patients who developed AKI later (2 among the 1st week AKI and 4 for AKIs developed after the 1st week) but none of the patients who had AKI on admission needed RRT. Anti IL-6 receptor antibody tocilizumab was used in patients who had high inflammatory response and its use was significantly more frequent for patients who developed AKI after 7th day. Pulmonary involvement (i.e. COVID pneumonia) was not different between the groups and there was not a statistically significant difference for secondary bacterial infections (Table-4).
Comparison between survivors and non-survivors
Survivors and non-survivors among patients who developed AKI were also compared. In-hospital stay length was not different for survivors and non-survivors. Those who died were older than those who didn’t. Patients who survived had similar diabetes or hypertension rates as patients who didn’t, while concomitant malignancies were more frequent in patients who died (Table-7).
AKI had 24,7% mortality in our patients who had eGFRs above 60 ml/min/1,73 m2 according to the baseline creatinine values. Baseline eGFRs were similar for survivors and non-survivors. AKI developed later in non-survivors and it lasted longer. Non-survivors had significantly higher initial CRP, LDH, ferritin and D-dimer levels while significantly lower hemoglobin and lymphocyte counts. (Table-7).
Patients who died had lower serum albumin levels than those who survived. Blood pH, oxygen saturation and arterial oxygen pressure levels were also calculated lower in patients who died. Hematuria or proteinuria (p=0,001; OR:2,4; 95% CI: 1,4 – 3,8 and p=0,015; OR:4,34; 95% CI:1,3 – 14,3 respectively) was more common in patients who died.
Among electrolyte disturbances hyponatremia and hypochloremia were not different between survivors and non-survivors. On the other hand, hypernatremia (p=0,000, OR:6,5 ; 95% CI:3,0 – 13,9) and hyperchloremia (p=0,002, OR:3,8; 95%CI: 1,7 – 8,4) were more common in patients who died. Both hyperphosphatemia (p=0,002, OR:3,3 ; 95%CI:1,6 – 6,9) and hypophosphatemia (p=0,000, OR:3,9; 95% CI: 2,0-7,9) were found to be significantly different between survivors and non-survivors. Hypomagnesemia was not different between survivors and non-survivors, however hypermagnesemia was more common in patients who died (p=0,000 , OR:7,3 ; 95% CI:3,2 – 16,5)
Patients who couldn’t survive had more acidotic blood pH (p=0,000; OR:7,0 95%CI: 3,0 – 16,4) and they also had more secondary bacterial infections (OR: 3,5 ; 95%CI: 1,9 – 6,4) than patients who survived. However, ferritin levels were similar in patients who had secondary bacterial infections and in those who hadn’t (n=24; 1120 ±691 vs n=62; 976 ± 109 ; p=0,548).
Urea-to-creatinine ratios which was checked both on the day of AKI and on the day of peak creatinine levels, were higher in non-surviving patients (p=0,02 and p=0,000 respectively).