DISCUSSION
In this retrospective analysis, we investigated the urinalysis data of Covid-19 patients, incidence and risk factors of AKI development, and mortality in-hospital in patients with Covid-19.
The importance of urine to show the severity of Covid-19 was firstly reported by Liu et al. They found significantly higher positive rates of hematuria, and proteinuria and higher urine pH in Covid-19 patients compared to healthy controls [41.2% vs. 22.2%, 28.6% vs. 11.1%, 6.27 ± 0.6 vs. 5.94 ±0.7, respectively],however in contrast urine specific gravity was found significantly lower in Covid-19 patients than healthy controls (1020 ± 0.007 vs. 1023 ± 0.007) [6]. Hirsch et al. found median value of urine specific gravity as 1020 (IQR, 1010-1020) [8]. We found urine specific gravity lower than previous reports especially in patients without glucosuria. Urine ph value was similar to the values reported previously [8,10]
Notably, glucosuria was found in 36.1% of patients similar to a previous report [12]. In our study most of the patients received corticosteroids. However; in only six patients (12.5%), renal glucosuria was found without serum glucose level not exceeding renal threshold for glucose similar to a previous report [18].It may be a result of proximal tubule injury in patients with Covid-19.
The rates of other urine parameters such as ketonuria and pyuria were found in our study as 15.6% and 9%, respectively. These changes had not been focussed in previous reports mostly. We found lower rates of pyuria than other studies [6,9]. Hirch et al. had found the frequency of pyuria more than our study in Covid-19 patients with AKI (36.5% vs. 15.9%) [8].
The high frequency of renal abnormalities including proteinuria and hematuria were reported in previous reports ranging between 20.3-89.8% and 6-81%, respectively [3,6-12,19]. Our study detected an incidence of proteinuria of 22.9% and hematuria of 22.1% on admission among the hospitalized patients with Covid-19.
The quantification and characterization of proteinuria were began to be investigated in recent studies. Huart et al. found proteinuria over 500 mg/g in 68 patients (44%) and they also found urine α1-microglobin (a marker of tubular injury) concentration higher than 15 mg/g in 89% patients suggesting tubular proteinuria [20]. In a recent analysis, Karras et al. found urine protein-creatinine ratio at admission ≥ 1g/g in 84 patients (42%) with a urine albumin-protein ratio <50% in 92% of patients. They also found urine retinol binding protein concentrations as ≥ 0.03 mg/mmol in 62% patients suggesting that Covid-19 associated proteinuria reflected low-molecular weight proteins, which cannot be reabsorbed by the proximal kidney tubule due to acute tubular damage [21].
Among our study population, we observed an incidence of AKI of 25.8% similar to other reports [11,22-24]. The reported rates of AKI are extremely variable; however, available evidence suggests that it likely affects >20% of hospitalized patients and >50% of patients in the ICU [25]. In a recent meta-analysis; the incidence of AKI was reported as 13.28% (162/1220) in all included studies [26].Differences may have resulted from definitions of AKI and the populations studied. The pathogenesis of AKI in patients with Covid-19 is likely multifactorial, involving both the direct effects of the SARS-CoV-2 virus on the kidney such as collapsing glomerulopathy, endothelial damage, coagulopathy, complement activation, and inflammation and the indirect mechanisms resulting from systemic consequences of viral infection or effects of the virus on distant organs including the lung, in addition to mechanisms relating to the management of Covid-19 [27]. Some studies reported the presence of viral particles within both the tubular epithelium and podocytes on electron microscopy, implying the direct infection of the kidney [28,29], others failed to demonstrate the presence of virus in the kidney [30-32]. In addition to direct pathophysiological mechanisms, renal dysfunction in the context of Covid-19 may also arise through the systemic effects of SARS-CoV-2 infection and critical illness. Volume depletion, exposure to nephrotoxins, increase in renal ven pressure and reduced filtration due to positive end expiratory pressure (PEEP), the release of cytokines, vasoactive substances and damage associated molecular patterns (DAMPs) from lung injury are also other mechanisms for kidney injury [27].
Risk factors of AKI in Covid-19 are diverse and multifactorial. A number of previous studies have suggested that the development of AKI in Covid-19 patients may be affected by multiple risk factors, such as older age, male sex, black race, comorbidities, increased CRP, proteinuria at admission, the need for ventilator support, use of vasopressor drug treatment [3,8,20,23,25]. On the basis of our multivariate logistic regression analysis; higher leukocytes, decreased eGFR and presence of proteinuria were independent predictors of AKI. As reported previously, we observed a high prevalence of hematuria and proteinuria in Covid-19 patients with AKI [3,12,19,21,22]. However in a recent study, they found no significant differences in proteinuria, hematuria and leukocyturia among patients with AKI compared with non-AKI patients [24].
Several mortality risk scores have been proposed to predict mortality in Covid-19 patients [33-35], most of which did not include an evaluation of kidney status. However, kidney indicators seem to be the main predictors of mortality. We found the highest mortality frequencies in patients with AKI compared to patients without AKI (38.1% vs. 5%,P =0.000) consistent with previous reports [19,23,36]. In a recent meta-analysis, Covid-19 patients with AKI had a significantly increased risk of death compared patients without AKI (OR 30.46, 95% CI 9.29-15.19) [26]. We also found that proteinuria were independently associated with mortality similar to previous reports [11,12]. Pei et al. showed higher overall mortality in the patients with renal involvement, including hematuria, proteinuria, and AKI, compared with that of patients without renal involvement (11.2% vs 1.2%,P =0.006) [3]. Cheng et al. reported the incidence of mortality in-hospital in the patients with elevated baseline serum creatinine on admission was 33.7%. They also found that proteinuria of any degree, hematuria of any degree, elevated baseline BUN, elevated baseline SCr, peak SCr> 133 mmol/l, and AKI over stage 2 were independently associated with mortality [7]. In another study Portoles et al. confirmed that elevated baseline SCr, previous chronic kidney disease, hematuria, and in-hospital AKI were independent risk factors for mortality in-hospital after adjusting for age, sex and comorbidity [9]. However; in a recent study, Ouahmi et al. reported that proteinuria was not found as an independent predictor for in-hospital mortality [24].
This study has several limitations. First, the number of patients included in this study is limited, and there were some missing data. Second, an accurate baseline serum creatinine and urine output was not available, which may have led to an under or overestimation of AKI or erroneous associations. We also were unable to distinguish patients who had preexisting proteinuria and hematuria prior to presentation from those who had it new-onset on admission due to lack of previous urinalysis in most patients. Third, disease severity was not defined because of missing data. Fourth, quantification of proteinuria could not be investigated.
Our study has some strengths. Mostly previous reports had urinalysis data based on dipstick results [3,7,9]. Our urinalysis results based on both dipstick and automatic sediment analyzers. Also we did not include patients with urinary catheterization, so hematuria may reflect more kidney involvement rather than urinary tract abnormalities.
In conclusion, proteinuria on admission is associated with development of AKI and in-hospital mortality in patients with Covid-19. We hence reinforce the suggestion that urinalysis may be useful for the evaluation of COVID-19 progression and early diagnosis of kidney damage before SCr rise. Early detection and effective intervention of kidney involvement may help to reduce development of AKI and to improve the vital prognosis of Covid-19.
Funding: None
Conflicts of interest: None
Availability of data and material: If requested.