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.