¹Department of Life Sciences, School of Basic Sciences & Research, Sharda
University, Greater Noida, Uttar Pradesh-201310, India.

²School of Medical Sciences & Research, Sharda ,Hospital, Sharda University
Campus, Greater Noida, Uttar Pradesh-201310, India.

³Shri Maneklal M Patel Institute of Science & Research, Kadi Sarva
Vishwavidhyalaya, Gandhinagar, Gujrat-382024, India.

⁴Virology Laboratory, Department of Microbiology, All India Institute of
Medical Sciences (AIIMS), New Delhi 110029, India.

Corresponding author email: vinodjoshidmrc@gmail.com

Article Publishing History

INTRODUCTION

Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-COV2) has now taken the shape of one of the most rampant human pandemics the world has ever faced. In India, there prevails the second wave of pandemic starting from 11^th February 2021 with a total of  178360849 cases and 3869384 as of today as updated on W.H.O’s Coronavirus (COVID-19) dashboard (https://covid19.who.int/ ), (Ranjan et al. 2021).

Due to huge number of cases being reported to hospitals every day, the treating clinicians are compelled to focus aggressively only on the anti-viral/anti-bacterial treatments to the patients with parallel attention on normalcy in vital levels of pulmonary oxygen saturation level, cardiac parameters and Blood Pressure levels. However, although many other parameters such as Liver Function Tests, Hematological parameters and Kidney Function Tests etc.

are being measured and recorded essentially among all the admitted patients, yet kidney function parameters are not paid attention to address them in the corresponding treatment protocols. It is well known that the human cell receptor of SARS-COV2 is Angiotensin-Converting Enzyme-2 (ACE-2) and it is very important enzyme of the RAS pathway (Renin-Angiotensin System) i.e. in regulating the blood pressure homeostasis of the body as well as in maintaining the fluid and salt balance in the body (https://www.rndsystems.com/resources/articles/ace-2-sars-receptor-identified), Acc Apr 2021)

This ACE receptor is expressed specifically on the lungs and also on the kidney, gastrointestinal cells, vascular epithelial cells, kidney and Leydig cells. The IFFC (International Federation of Clinical chemistry and Laboratory Medicine) Guidelines on COVID-19 highlights the need of monitoring creatinine levels in critical COVID-19 patients so as to diagnose any injury to kidney at an early stage (IFCC guide on COVID-19, 2020).^. The observations reported in the present study are in concurrence with the IFFC guidelines. Previous studies have reported that in the SARS-COV 1, 2003 strain and the Middle East respiratory syndrome (MERS) infection, there were cases with Acute kidney injury (AKI) and subsequent mortality of cases (Elias & Benito, 2018, Cheng et al. 2020; Naicker et al. 2020).

The present study highlights the association between the recovery/mortality of Covid-19 patients with their Kidney Function parameters and reports that surviving patients showed normal and not surviving patients showed abnormal kidney function parameters. Crucial kidney function parameters viz; Blood urea and creatinine level needs addressal and after more number of studies their treatment could be included in treatment protocols of COVID-19 patients. Similarly, the observations reported of Sodium and potassium levels among “survivors” and “dead” sensitized further clinic-basic studies on roles of SARS-COV2 in blocking essential ion channels of human physiological system.

MATERIAL AND  METHODS

A study of association between Kidney Function Tests and survival/mortality of COVID-19 patients was undertaken among patients reporting in Noida and Greater Noida, UP, India. Surviving and Dead cases were chosen at random for the study. Few investigations were done in the residential society as per the information of COVID-19 patients obtained from the society notifications/news board. Few samples were also studied among students, staff and faculties in Sharda University who had either been a patient of COVID-19 or had any family members infected with COVID-19 in the past.

Some information was collected from the patients records of Sharda hospital, Greater Noida, UP, India after obtaining appropriate permission from the Hospital administration. The contact details of the COVID-19 patients obtained from the above survey was tabulated and patients were contacted telephonically. The aims and objectives of this study were telephonically conveyed to the patients or their family members (who so ever were available on phone for the conversation). After taking their verbal consent for participation in the study, their Kidney function tests parameters were noted down along with other clinical parameters.

RESULTS AND DISCUSSION

A total of 76 patients were included in the study which comprised of 36 “Recovered” patients and 40 “Dead” cases (Table 1 &2). Association of Kidney Function parameter with the Recovery from COVID-19 infection: Of the 36 study patients, 5.5% (2 patients; 1 Male, 1 Female) were in the age group of 0-20 years; 33.3% (12 patients; 7 Males, 5 Female) were of the age 21-40 years;  27.7 % (10 patients; 5 Males, 5 Females) were of the age 41-60 years and 30.55 % ( 11 males &  2 Females) were above 61years of age. (Table 1)

Association between Recovery of patients and Blood Urea level: It was observed that of the total 36 “Recovered” patients, 30 patients (83.3%) did not have hyper levels of urea (non-hyper level) in their blood establishing the optimum functioning of kidney with respect to Urea extraction from blood. Only 6 patients (16.6%) who recovered had hyper/higher levels of blood urea.  (Fig. 1).

Association between Recovery of patients and Blood Creatinine level:Of the total 36 patients studied who recovered from infection, 32 patients (88.8%) had non-hyper levels of Creatinine in their blood establishing the optimum functioning of kidney with respect to Creatinine extraction from blood. Only 4 patients (11.11%) who recovered had higher levels of blood creatinine.  This comprised of 2 females (56& 65years respectively) and 2 males (65& 78 years respectively). (Fig.1).

Association between Recovery of patients and Blood Uric acid level: Out of 36 patients who recovered from COVID-19, 8 (22.2%) patients had hyper levels of Uric acid whereas 28 patients (77.8%) showed non-hyper levels of Uric acid in the blood. The 8 patients included 4 males (between 46-65 years) and 4 females (between 56-75 years) (Fig. 1).

Figure 1: Schematic presentation of degree of association between kidney function values
(Urea, Creatinine and Uric Acid) and recovery/mortality of COVID-19 patients

Association between Recovery of patients and Blood Sodium level: The values observed in the recovered patients indicated that 12 (33.3%) patients (8 males and 4 female patients of age 41 to 78 years) had low levels i.e. between 130 to 136mg/Eq/L. Higher values were observed in 2 (5.55%) patients (1 male patient of 46 years and 1 female of age 75years) the value being 148 and 150 mgEq/L respectively i.e. 18 patients (61.11%) had normal sodium levels (Fig. 2).

Figure 2: Schematic presentation of degree of association between Electrolyte values
(Sodium, Potassium and Chloride) and recovery/mortality of COVID-19 patients

Association between Recovery of patients and Blood Potassium level: Higher values of Potassi:um were observed in 11 (30.55%) patients (six female of 23-59 years; 5 males of 23-65 years), the value was found to be between 5.3 to 10.0 mgEq/L. No low values were observed in the recovered patients, the remaining 25 patients had normal levels of potassium account to 69.44%. (Fig. 2).

Association between Recovery of patients and Blood Chloride level:The values observed in the recovered patients indicated that one male patient (2.7%) had low level (age 78 years) of Chloride while Higher values were observed in 9 (25%) patients; six females (age 23-75 years), 3 male patients (age 46-65 years). The remaining 26 (88.88%) had normal chloride levels (Fig. 2).

Table 1. Values of Kidney function parameters obtained from patients recovered from COVID-19 infection.

S.No	Patient code	Age	Sex	Day of recovery/ discharge after hospitalization	Kidney Function Test			Electrolytes
					Urea (mg/dl) Ref level: 20.0-43.0 mg/dl	Creatinine (mg/dl) Ref level: 0.52-1.04 mg/dl	Uric acid (mg/dl) Ref level: 2.50-6.20 mg/dl	Sodium (mEq/L) Ref Level: 137.0-145.0 mgEq/L	Potassium (mgEq/L) Ref Level: 3.50-5.10mgEq/L	Chloride (mgEq/L) Ref level: 98.0-107.0mgEq/L
1.	SCR 5	41	M	8th	38.5	0.5	2.2	136	3.7	98
2.	SCR 7	56	F	9th	99.7	1.1	7.1	138	4.6	103
3.	SCR 9	35	M	10th	19.2	0.8	5.6	142	4.2	105
4.	SCR 13	62	M	10th	30.90	0.70	4.0	139	4.4	103
5.	SCR 15	23	F	11th	19.20	0.4	3.5	140	4.4	105
6.	SCR 16	31	F	10th	16.2	0.5	1.7	139	4.4	108
7.	SCR 17	25	F	11th	14.8	0.6	2.9	140	3.8	104
8.	SCR 18	35	F	9th	22.0	0.5	2.3	139	4.1	104
9.	SCR 19	5	F	6th	20.5	0.2	3.0	140	4.1	105
10.	SCR 20	65	M	8th	20.8	0.9	5.2	141	4.2	109
11.	SCR 21	29	M	10th	25.1	0.7	5.2	145	5.0	107
12.	SCR 22	37	M	3rd	23.1	0.5	4.4	138	4.8	102
13.	SCR 25	46	M	8th	24.7	0.9	6.7	148	4.9	109
14.	SCR 26	48	F	5th	29.7	0.5	1.9	136	5.3	109
15.	SCR 27	65	M	14th	125.3	3.7	9.6	132	7.7	109
16.	SCR 28	51	M	7th	23.4	0.8	7.1	141	5.1	110
17.	SCR 31	78	M	13th	61.4	1.1	5.2	135	4.1	97
18.	SCR 32	58	F	11th	30.4	0.6	7.3	135	4.0	101
19.	SCR 35	62	M	8th	25.6	0.9	5.8	140	5.0	102
20.	SCR 37	65	M	11th	26.5	1.0	7.0	133	5.4	102
21.	SCR 41	23	M	7th	20.9	0.8	3.9	139	5.8	104
22.	SCR 44	23	F	13th	17.5	0.6	3.9	145	5.9	110
23.	SCR 45	21	M	13th	17.9	0.6	5.2	139	10.0	105
24.	SCR 53	59	F	18th	35.0	0.7	10.0	133	5.8	98
25.	SCR 54	62	M	3rd	24.3	0.6	5.1	135	5.4	101
26.	SCR 55	74	M	9th	40.0	0.9	5.1	134	4.3	98
27.	SCR 56	75	F	9th	41.4	3.0	10.0	150	5.3	112
28.	SCR 60	52	M	7th	82.8	0.9	5.0	137	4.3	104
29.	SCR 61	–	F	2nd	21.3	0.6	5.9	139	5.9	106
30.	SCR 62	41	F	8th	40.1	0.4	5.8	144	5.2	108
31.	SCR 64	35	M	30th	53.1	0.8	4.5	131	5.1	100
32.	SCR 65	62	M	4th	34.2	0.7	3.9	133	4.1	100
33.	SCR 67	72	F	4th	24.5	0.5	5.5	130	3.5	99
34.	SCR 72	14	M	10th	25.9	0.3	3.6	138	4.4	105
35.	SCR 73	40	M	8th	22.9	0.7	5.2	139	5.0	103
36.	SCR 74	49	M	12th	59.4	1.0	5.4	138	4.3	105

Association of Kidney Function parameters with the Mortality of patients from COVID-19 infection: Of the total 40 patients who did not survive, their age ranged from 23 to 99 years. 7.5% were of age between 21-40 years (one female & 2 male), 30% were of the age 41-50 years (5 females & 7 males) and 55 % were above 61 years of age (7 females; 15 males) (Table 2).

Association between Mortality of patients and Blood Urea level: Referring to the level of urea to be 20.0-43.0 mg/dl in a healthy person, the values were analyzed among 40 “Dead” patients. It was found that hyper values of blood urea were observed in 29 patients (72.5%) out of the 40 patients (8 females of age 24 to 99 years and 19 males of age 46 to 82 years). The values ranged from 43.2. to as high as 221.8mg/dl. Only 11 (27.5%) “Dead” patients had non-hyper levels of urea (Fig. 1).

Association between Mortality of patients and Blood Creatinine: The values observed for blood creatinine in the “Dead” cases indicated that 16 patients (40%) (3 females and 13 males) had hyper values of creatinine ranging from 1.1 to 7.0mg/dl while 24 patients (60%) had non-hyper levels of creatinine (Fig. 1).                                                                   

Association between Mortality of patients and Blood Uric acid: The values observed in the dead patients indicated that 13 patients (32.5%) (2 females, 10 males and 1 UnK case) had hyper values. The age group was 24 -63 years in female patients, while in male patients it ranged from 57 to 82 years (within 6.2 to 13.9mg/dl range).  However, there were 27 (67.5%) of “Dead” patients who had non-hyper levels of uric acid (Fig. 1).

Association between Mortality of patients and Blood Sodium:The values of blood sodium observed in the patients who did not survive indicated 16 (40%) patients with low Sodium values (5 females, 11males; age group 24-66 years and 53 to 82 years respectively). The values were found to be between 115-136mgEq/L. Higher values were observed in three (7.5%) male patients, of 40, 65 and 67 years with values between 149-153mgEq/L. Remaining 21 (52.5%) had normal levels of sodium (Fig. 2)

Association between Mortality of patients and Blood Potassium:The Potassium levels observed in the patients who did not survive, indicated that two (5%) male patients of age 71 & 80 years had low levels of potassium (2.6 & 2.8mgEq/L respectively). Higher values were observed in six (15%) patients; 5 males & 1 UnK of age between 58-82years, the values were between 5.1-6.5 mgEq/L. Remaining 32 (80%) patients showed normal levels (Fig. 2).

Association between Mortality of patients and Blood Chloride: The Chloride values observed in the patients who did not survive indicated low values (94-96mEq/L) in 4 (10%) patients i.e. two females and two male patients (age between 57-66years). Higher values were observed in 12 (30%) patients; one UnK with 108mEq/L; three females (age 24-74 years), had values between 110-114mgEq/l. The 6 male patients (age 23-80 years) had values between 114-117mgEq/l. Normal values were seen on 24 (60%) patients (Fig. 2).

Table 2. Values of Kidney function parameters obtained from patients who did not survive the COVID-19 infection.

S.No.	Patient code	Age	Sex	Day till hospitalized	Kidney Function Test			Electrolytes
					Urea (mg/dl) Ref level: 20.0-43.0 mg/dl	Creatinine (mg/dl) Ref level: 0.52-1.04 mg/dl	Uric acid (mg/dl) Ref level: 2.50-6.20 mg/dl	Sodium (mEq/L) Ref Level: 137.0-145.0 mgEq/L	Potassium (mgEq/L) Ref Level: 3.50-5.10mgEq/L	Chloride (mgEq/L) Ref level: 98.0-107.0mgEq/L
1.	SCD 1	60	M	5th	234.9	7.0	13.3	124	5.6	98
2.	SCD 2	63	F	6th	52.6	0.8	13.7	142	5.0	99
3.	SCD 3	80	M	5th	86.6	0.8	4.3	136	3.8	104
4.	SCD 4	70	M	4th	221.8	4.4	10.0	137	6.2	105
5.	SCD 5	51	F	3rd	39	0.8	3.5	140	3.6	107
6.	SCD 7	52	F	9th	114.8	3.4	2.5	141	4.1	106
7.	SCD 8	24	F	4th	63.5	0.6	6.4	134	3.9	110
8.	SCD 9	80	F	4th	52.4	0.6	4.8	145	2.8	107
9.	SCD 10	46	M	6th	123.4	3.3	3.2	143	5.1	116
10.	SCD 11	63	M	5th	116.3	1.0	3.9	144	4.8	117
11.	SCD 19	23	M	9th	36.1	0.7	5.5	140	5.0	113
12.	SCD 22	67	M	8th	29.7	0.8	5.9	137	4.2	103
13.	SCD 23	57	F	7th	36.3	1.1	5.0	135	4.3	96
14.	SCD 24	68	F	2nd	47.8	0.5	5.1	140	3.5	98
15.	SCD 26	67	M	5th	70.3	0.9	6.3	135	3.5	99
16.	SCD 27	70	M	8th	112.7	10.6	4.8	123	4.1	94
17.	SCD 28	67	M	6th	87.0	3.0	5.8	149	3.6	115
18.	SCD 29	53	M	3rd	23.5	0.8	4.5	135	5.0	106
19.	SCD 30	71	M	6th	55.2	1.5	7.8	141	2.6	97
20.	SCD 31	65	M	10th	74.1	0.9	3.8	147	3.5	102
21.	SCD 32	58	M	4th	85.1	0.8	7.2	138	5.7	99
22.	SCD 33	67	M	5th	35.5	1.1	6.6	133	5.6	97
23.	SCD 34	54	M	5th	23.2	0.6	3.1	128	4.5	98
24.	SCD 38	57	M	2nd	43.2	1.5	6.6	137	4.4	95
25.	SCD 42	60	F	3rd	67	2.2	5.1	134	4.7	110
26.	SCD 45	–	–	5th	112	1.0	13.9	145	6.5	108
27.	SCD 46	54	M	4th	36	1.5	4.2	133	4.6	105
28.	SCD 49	61	M	1st	55.7	0.82	–	133	4.5	101
29.	SCD 52	66	F	8th	45.2	0.9	5.4	127	3.6	94
30.	SCD 53	66	M	3rd	75.7	1.5	6.9	139	4.4	104
31.	SCD 55	40	M	6th	42.3	0.7	2.8	153	4.2	116
32.	SCD 57	78	M	2nd	91.8	5.7	5.3	139	4.3	104
33.	SCD 58	59	F	2nd	25.6	0.6	5.1	136	5.0	105
34.	SCD 60	74	F	6th	86.4	0.8	4.8	145	3.3	114
35.	SCD 61	80	M	5th	47.7	0.7	3.3	139	3.1	115
36.	SCD 62		M	9th	44.8	0.7	2.4	137	4.2	98
37.	SCD 64	99	F	3rd	70.7	0.9	4.8	144	3.9	107
38.	SCD 67	82	M	2nd	207.7	1.6	7.3	115	5.6	111
39.	SCD 68		M	4th	54.3	0.6	4.3	133	4.7	99
40.	SCD 69	82	M	4th	133.9	3.0	7.8	145	4.2	112

Relative association of Blood Urea, Creatinine and Uric acid with survival/mortality of patients: Blood Urea: It was observed that average percentage of the association between hyper blood urea and recovery/mortality of the cases was 77.9%. As 83.4% of “Recovered” patients did not show hyper urea level whereas 72.5% of “Dead” patient showed hyper urea levels.

Blood Creatinine: It was observed that average percentage of the association between hyper blood creatinine and recovery/mortality of the cases was 64.4%. 88.8% of “Recovered” patients did not show hyper creatinine level whereas 40.0% of “Dead” patient showed hyper creatinine levels.

Uric Acid: It was observed that average percentage of the association between hyper blood uric acid and recovery/mortality of the cases was observed to be 55.1%. 77.7% of “Recovered” patients did not show hyper uric acid levels whereas 32.5% of “Dead” patient showed hyper creatinine levels.

Association of Electrolyte levels in survival/mortality in COVID-19 patients: Sodium & Potassium level: An inverse association of Sodium and Potassium levels were observed in study subjects. Of the total number of 36 patients who recovered, it was observed that maximum patients were having Low levels of sodium and high levels of potassium (33.33% and 30.55% respectively) when compared to the high and normal values. Similarly, of the total number of 40 patients who died, maximum patients were reported with Low levels of sodium and high levels of potassium (40% and 15% respectively) when compared with their high and normal values. Chloride level: Chloride levels also had trend like that of potassium levels. Maximum number of patients who survived and who died were comparatively more (25% and 30% respectively)  

Present work has been undertaken to study association of kidney function parameters with the survival/mortality of COVID-19 patients. After careful observations and analysis of Kidney Function parameters among the categories of “Recovered” and “Dead” cases, we observed that most crucial of these KFT parameters is the level of Blood Urea followed closely by Blood Creatinine level among the two categories of COVID-19 patients. The degree of association observed between blood urea level versus survival/mortality of patients emerged to be the most significant observation.

Our preliminary study reveals that need for addressal and/or correction of blood urea level among patients may be considered for possible inclusion into the COVID-19 TREATMENT protocol through appropriate clinical interventions. Fundamentally, when protein is broken down in the body, then urea is made in the liver and is then passed out of the body in the form of urine, which indirectly amounts to the level of nitrogen in the body. So if there is elevated levels of Urea in the blood it is as indication of inefficient kidney functions, which may impact the blood chemistry to lead to cardiac and/or pulmonary problems enhancing mortality of COVID-19 patients.

The second important observation emerged out of present study is a high degree of association of Serum Creatine level with the survival and mortality of patients. The degree of association between creatinine and survival/mortality of patients was computed to be 64.4 which reveals that treatment to keep normal creatinine after studying the observed value of this parameter among patients has to be the part of COVID-19 treatment protocol. Creatine is yet an another amino acid which we get through dietary intake. This is also made in the liver and provides energy to the body. It is also present in muscles and when the body utilizes creatine as an energy source, then creatinine is expelled out of the body as waste material (https://www.medicalnewstoday.com/articles/322380) (Acc May 2021).

 Elevated levels of creatinine in blood may be correlated with decreased excretion and besides this Creatinine is also measured to correlate the Glomerular filtration rate (GFR) in our body (Thomas 2005).  The IFFC (International Federation of Clinical chemistry and Laboratory Medicine) Guidelines on COVID-19 highlights the need of monitoring creatinine levels in critical COVID-19 patients so as to diagnose any injury to kidney at an early stage (IFCC guide on COVID-19, 2020).^. The observations reported in the present study are in concurrence with the IFFC guidelines. Previous studies have reported that in the SARS-COV 1, 2003 strain and the Middle East respiratory syndrome (MERS) infection, there were cases with Acute kidney injury (AKI) and subsequent mortality of cases (Cheng et al. 2020; Naicker et al. 2020).

Many viruses including SARS-COV2 have been reported to show ‘viroporin’ activity for which it depends on the ion channels present on the host cells (Charlton et al. 2020; Neiva et al. 2012; Neiva et al. 2015; Royle et al. 2015) as it does for its replication and dissemination activities. As it causes infection and complication when it enters specific cell or tissue, similarly it may also cause impaired ion-channels and may contribute to internal imbalance or disturbances.

Of the whole array of 300 ions channels known in humans (Yu et al. 2005), there are many channels which have been studied for their involvement either in viral entry or in replication or in dissemination and also in the involvement in dysfunctions generalized as ‘Channelopathies’ and hence causing chaos in the ion channels associated with the nervous, musculoskeletal, cardiovascular, immune systems, (Kim, 2014; Elias & Benito, 2018; Vaeth & Feske, 2018,  Charlton et al. 2020).

 It has also been known that the E protein of the SARS-COV2 virus has more affinity for sodium ions than potassium ions (Kai et al. 2016; Melton et al. 2002), while the 3a protein have a tendency to form ion channel and thus aid in virus dissemination (Lu et al. 2006). The low levels of sodium as seen in the patients who did not survive may indicate utility of ion channels by the virus and thus leading to decrease in the sodium channels availability for the human system to perform its normal functioning such as disturbance in the RAS/homeostasis pathway.

The fact that low levels of sodium had been observed in recovered patients also can be supported by the fact that may be use of ion channel blockers are hypertensive medication may have contributed as a modulator of this viral activity. This necessitate further studies of adding ion channel modulators in the treatment protocol (only after careful analysis of KFT test reports) in complicated cases. The Dysregulation of sodium channels specifically of the respiratory tract has been observed in Human Respiratory Syncytial virus (Chen et al. 2009). This observation also focuses studies to be extended on understanding role of SARS-COV2 with chloride and potassium levels too.

CONCLUSION

All the parameters i.e. urea, creatinine, uric acid and electrolytes are very important and speak for  their individual existence and persistence within the human  body, but the fact needs to be considered whether these are symptoms prior to viral infection or whether these are the  post effects of COVID-19 infection. The findings of the present study thus highlight an important observation which needs to be considered to improvise renal treatment regime of the COVID-19 patients. Preliminary observations reported in the present paper sensitizes to further understand and confirm the reported association of kidney function and recovery/mortality of patients and if proved the treatment protocol of COVID-19 may be considered for possible modification.

Disclosure: The authors declare that there are no conflicts of interest in this work.

ACKNOWLEDGEMENTS

 We thank Dr Ashutosh Niranjan, Medical Superintendent, Sharda Hospital for kindly providing us with data for analysis of this work and also to the staff and students who have worked in providing us the data.

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