Effect of novel coronavirus disease 2019 infection on chronic kidney disease G1-G5, G5 Dialysis and G5 Transplantation

Background: The pneumonia caused by the 2019 novel coronavirus (SARS-CoV-2) is a highly infectious disease that causes lethal disease and multiorgan failure. The aim of this research is to investigate association between coronavirus disease 2019 (COVID-19) infection and kidney dysfunction. Methods and Materials: In this retrospective study, sixty-eight patients with kidney dysfunction and COVID-19 infection were investigated. Clinical features, laboratory data at initial presentation, management and outcomes were collected.The paper has written based on searching PubMed Central and Google Scholar to identify potentially relevant articles. Median, percentage, mean ± standard deviation (SD), two-tailed t and chi-square and Cohen (cid:0) sd tests were used for statistical analyses. Moreover, relative risk, odds ratio, pearson (cid:0) s correlation for statistical analyses were used. Results: The average age of patients at time of diagnosis in COVID-19 nephropathy was 52.04 ± 14.42 years (ranging from 24 years to 88 years). There was not statistical signicance correlation between lymphocytopenia and serum creatinine (SCr) in COVID-19 nephropathy (R 2 =0.063; p-value= 0.33). Effect size of elevated IL-6 on decreased estimated glomerular ltration rate (eGFR) in COVID-19 nephropathy was assessed 0.656 (medium effect size). Relative risk and odds ratio of acute kidney disease (AKD) in COVID-19 nephropathy were assessed 0.57 and 0.4, respectively (p-value: 0.422). Correlation between SCr changes and time of emergent acute kidney injury (AKI), AKD and chronic kidney disease (CKD) was assessed with R 2 of 0.0003 and p-value of 0.94 (not signicant). Conclusion: The present study revealed medium effect size of elevated IL-6 on decreased eGFR. Future clinical research is required for investigating novel unknown ndings in COVID-19 nephropathy. moderate and and severe less than 500/microL. Lymphocytosis is dened as an ALC > 4000 cells /microliter (also expressed as >4000/mm 3 or >4.0 x 10 9 /L). Lymphocytopenia has been variously dened in older children and adults as an ALC <1000 or <1500 cells/microL. Circulating blood lymphocytes include populations of T cells, B cells, and natural killer (NK) cells. Their normal relative proportions in the blood are: T cells (eg, CD3 + cells) - 60 to 80 percent, B cells (eg, CD20 + cells) - 10 to 20 percent, NK cells (eg, CD56 + cells) - 5 to 10 percent. The normal relative proportions of T cell subtypes in the blood are: Helper/inducer T cells (ie, CD4 + T cells) - 60 to 70 percent, Suppressor/cytotoxic T cells (ie, CD8 + T cells) - 30 to 40 percent. Alanine aminotransferase (ALT) > 29 to 33 IU/L in male and > 19 to 25 IU/L in female is dened abnormal serum aminotransferase levels. An aspartate aminotransferase (AST) cut off of 10 to 40 IU/L in for men and 9 to 32 IU/L in women is considered abnormal value. The normal range of lactate dehydrogenase (LDH) is between 140 to 280 U/l. Normal serum albumin is dened 3.5-5.5 g/dl. Procalcitonine is a biologic marker that are sometimes used for distinguish between bacterial and nonbacterial causes of pneumonia. PCT is a peptide precursor of calcitonin that is released by paranchymal cells in response to bacterial toxins. It increases in bacterial infections and down-regulated in viral infections. It measures by kryptor assay and the immunoluminometric (LUMI) assay. Normal value for procalcitonine in males is ≤ 19 pg/mL or ≤ 19 ng/L [international system of units (SI units)] and < 0.5 ng/ml. Amounts of Data were entered in Microsoft software. Categorical variables are recorded as frequency (N) and percentage (%). The continuous variables were determined as to whether they were normally distributed using the kolmogorove-smirnov or shapiro-wilk test. Continuous variables with normal distribution reported as mean ± standard deviation (SD). Nonparametric variables are expressed as median and interquartile range (Q1, Q3 and IQR). Comparisons between continuous variables with normally distributed (ND) data assessed by two-tailed one-sample t test analysis. Relative risk (RR) and Odds (Ods) ratio were used for assessing effect measures of risk factor on outcomes of disease. Furthermore chi-square test for association between risk factor (Covid-19) and outcomes was used. Effect size of intervention was assessed using Cohens (cid:0) d test. Correlation between two parametric and nonparametric variables were assessed using Pearson (cid:0) s and spearson (cid:0) s tests. This correlation between nonparametric (X) and parametric (Y) variables was assessed linear regression analysis. Signicance was assessed with p-value of < 0.05. nephropathy there were normal SCr in ve of sixty-eight patients (5/68, 7.3%) with covid-19 nephropathy. There were normal CRP found in four of sixty-eight (4/68, 5.8%) patients with covid-19 nephropathy and elevated CRP was detected in six of sixty-eight patients (6/68, 8.8%) with covid-19 nephropathy. improved in eight of sixty-eight patients (8/68, 11.7%) with covid-19 nephropathy and decreased in four of sixty-eight patients (4/68, 5.8%). There were multiorgan failure (MOF) in one of sixty-eight patients (1/68, 1.4%) with nephropathy and symptom in one of sixty-eight patients variable (1/68, 1.4%). There was O2 saturation ³ 95% in four of sixty-eight patients (4/68, 5.8%) and O2 saturation of 90% found in two of sixty-eight patients (2/68, 2.9%) with covid-19 nephropathy. Resolution of CXR abnormalities found in four of sixty-eight patients (4/68, 5.8%) and mild improvement found in two of sixty-eight patients (2/68, 2.9%) with covid-19 nephropathy. there was unresolved pulmonary abnormality in CXR in one of sixty-eight patients (1/68, 1.4%). were unmentioned CXR during follow up in sixty-one of sixty-eight patients (61/68, 89.7%) with covid-19 nephropathy. Fifteen of sixty-eight patients 22%) with covid-19 nephropathy follow up sixty-eight 4.4%) with covid-19 nephropathy during f/u. Leukocytosis and leukopenia found in two of sixty-eight of patients (2/68, 2.9%) with covid-19 nephropathy. Decreased LDH found in three of sixty-eight patients (3/68, 4.4%) with covid-19 nephropathy and elevated LDH was seen in two of sixty-eight patients (2/68, 2.9%) with covid-19 nephropathy. There were normal lymphocyte in one of sixty-eight patients (1/68, 1.4%) and elevated lymphocyte count in four of sixty-eight (4/68, 5.8%) patients with covid-19 nephropathy during f/u. There was elevated d-dimer in two of sixty-eight patients (2/68, 2.9%) with covid-19 nephropathy. There was elevated procalcitonine in one of sixty-eight patients (1/68, 1.4%) with covid-19 nephropathy. There was decreased PT in one of sixty-eight patients (1/68, 1.4%) with CoViD-19 nephropathy. Twenty-one of sixty-eight patients (21/68, 30.8%) with covid-19 nephropathy were discharged from hospital. There were elevated ferritin in three of sixty-eight patients (3/68, 4.4%) with covid-19 nephropathy. Hypocapnia found in two of sixty-eight patients (2/68, 2.9%) with covid-19 nephropathy. Anemia found in three of sixty-eight patients (3/68, 4.4%) with covid-19 nephropathy. Hypobrinogenemia found in two of sixty-eight patients (2/68, 2.9%) with covid-19 nephropathy. Ten of sixty-eight patients with covid-19 nephropathy stayed on HD during follow up and one of sixty-eight patients with covid-19 nephropathy remained on RRT but its type was not charactererized. One of assessed 0.36 (not signicant). There proteinuria using spot UPCR in one of sixty-eight patients (1/68, 1.4%), three patients using 24-hr urine collection (3/68, 4.4%) with mean average of 2.61±1.58 gr/24hr and one patient had trace proteinuria using urinalysis (1/68, 1.4%) with covid-19 nephropathy during follow up. UTI was seen in one of sixty-eight patients (1/68, 1.4%) with covid-19 nephropathy. there was not correlation between lymphocytopenia and elevated serum creatinine. Moreover, effect size of elevated IL-6 on decreased eGFR was medium. Relative risk and odds ratio of covid-19 in emerging acute kidney disease in covid-19 nephropathy was assessed 0.57 and 0.4, respectively. Future research is needed for investigating more unknown ndings about covid-19 nephropathy.


Introduction
Viral pneumonia by novel coronavirus-19 (SARS-CoV-2) has been emerged in December 2019 in Wuhan, Hubei province, China for the rst times [1].This new disease has been named novel coronavirus disease-2019 (nCOVID-19) by world Health Organization.Coronavirus belongs to coronaviridae family, Nidovirales order and reveals with crown-like projections on its surface.In the late 1960s, it has been isolated from patients with common cold and identi ed it as B814 by electron microscopy.This virus comprise alpha (a), beta (b), gamma (g) and delta (d) subgroups.The main reservoirs of virus include bats, palm civets, livestock and animals.These viruses were assumed to transmit among animals till outbreak of SARS in 2002 year in the Guangdong, china.Thereafter, outbreak of Middle East respiratory syndrome coronavirus (MERS) has been emerged in Middle Eastern countries.In recent outbreak in china, it was thought to have originated from the Hunan seafood market at Wuhan in china.Some have belief that this virus has evolved from an unknown species of bat at a Wuhan wet animal market in southern china.The patients were diagnosed with pneumonia of unknown etiology and were related to seafood market.Gradually, disease was increased at that region and it was detected in those had not gone a journey to seafood market and at that time purposed possible of person-to-person transmission.Coronavirus is a single stranded (positive sense) ribonucleic acid (RNA) Betacoronavirus, enveloped (E-protein) with club shaped/pear shaped/petal shaped glycoprotein projections (S-protein).This virus is spherical or pleomorphic shape with 80-120 nm size and include spikes which are made hemagglutinin esterase.The S-protein mediates the viral attachment and entry to endoplasmic reticulum.SARS-CoV-2 maintains the classic coronavirus structure like the presence of spike protein and expression of other nucleoproteins, polyproteins and membrane proteins such as RNA polymerase, 3-chymotrypsin-like protease, papain-like protease, helicase, glycoprotein and accessory proteins.Pandemic u phase include phases 1-3 that predominantly are animal infections and few human infections.Phase 4 comprise sustained human to human transmission and phase 3-6/pandemic with widespread human infection.In post peak there is possibility of recurrent events and in post pandemic there is disease activity at seasonal levels [2].

Objectives
How this study might work SARS-CoV-2 (COVID-19) in persons with chronic comorbidities can lead to critical illness easily or cause death.Patients with underlaying disease e.g.cardiac, lung, liver and kidney damage are at higher risk of COVID-19 infection rather than healthy patients.End-stage kidney disease patients are not exceptional this rule due to immune system suppression and poor outcomes from this viral infection.Hence, close identi cation of association between this viral infection and kidney dysfunction leads to new mechanisms in pathogenesis and novel therapeutic agents.This work causes less spread and limitation of viral infection.
Why does this research SARS-CoV infection evolved in china in 2002 year and then SARS-CoV-2 has been spreaded in Dec 2019.SARS-CoV-2 has been isolated in saliva, nasopharynx and lower respiratory tract samples.Viral RNA has been found in the plasma of 15% of the most severely affected patients and viral detection in stool raises the possibility of fecal transmission.Because rapid spread, asymptomatic nature and high mortality of this viral infection has been caused to obtain speci c and more knowledge about disease to prevent this viral infection.

Methods
Eligibility criteria

Type of studies
The search identi ed 1391 full-text articles via electronic search in google scholar and PubMed central databases.Therefore total records of 1391 fulltext articles were screened and seven articles were deduplicated (1384).Then 202 full-text articles were eligible and 1182 articles were excluded due to not related subject.Therefore, 68 records in 43 published articles included and 159 articles were discarded due to non-case reports.These 43 articles included 68 case reports that were examined 68 patients of kidney disease with CoViD-19 infection.These participants were enrolled for systematic review and meta-analysis synthesis.

Type of participants
Patients with kidney dysfunction including acute kidney injury (AKI), acute kidney disease (AKD), chronic kidney disease (CKD) and kidney replacement transplants (KRT) that were infected to SARS-CoV-2 were enrolled in this research.

Primary outcomes
Risk of AKI, AKD, CKD, kidney failure (KF) progression to kidney replacement therapy (KRT) and graft loss, ICU admission, mechanical ventilation and death were primary outcomes in this study.

Secondary outcomes
Urinary tract infection (UTI), decreased eGFR and elevated urinary albumin to creatinine ratio (UACR) for detecting proteinuria were secondary outcomes in this study.

Information sources
The paper has written based on advanced searching via PMC and Google Scholar databases to identify articles published since inception to May 2020.

Electronic search
The mentioned search performed with search terms of kidney and CoViD-19, CoViD-19 nephropathy in this research.

Searching other resources
The author reviewed references of all included articles and performed handsearching of related journals to identify the additional relevant studies.

Study selection
The search strategy was used to obtain titles and abstracts of studies that might be relevant to the review.The 401 plus 990 titles and abstracts were screened via electronic search in PMC and Google Scholar by author, respectively.Total records of 1391 articles were screened and after deduplication 1384 articles identi ed.Of them, 1182 articles were excluded due to non-related subject, review articles, others and 202 full-text articles were considered for eligibility.However studies and reviews that might include relevant data or information on studies were retained initially.The 159 articles were excluded and then 43 published articles that were examined 68 patients with covid-19 infection and renal dysfunction were included for qualitative and quantitative synthesis.

Data extraction and management
Data extraction was carried out by author and studies which reported in journals as non-English language were translated before assessment.Where more than one publication of a study existed, reports were grouped together and the publication with the most complete data was included.

Data items
All patients with clinical, laboratory and radiologic presentations of CoViD-19 infection and decreased eGFR with or without positive test for CoViD-19 in sputum, stool, urine, peritoneal dialysis uid and tissue biopsy-proven specimens were considered in this research.Demographic and clinical features such as age, sex, different symptoms and physical signs were extracted from this study.Furthermore, biochemical variables of serum creatinine (SCr), eGFR, urine protein, nucleic acid testing as quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) at initial presentation and following days, imaging, management and outcomes were collected.
De nition of kidney dysfunction AKI, AKD and CKD can form a continuum whereby initial kidney injury can lead to persistent injury eventually leading to CKD.AKI is de ned as an abrupt decrease in kidney function occurring over 7 days or less whereas CKD is de ned by the persistent of kidney disease for a period of > 90 days.AKD is de ned as acute or subacute damage and/or loss of kidney function for a duration of between seven and 90 days after exposure to an AKI initiating event.Recovery from AKI within 48 h of the initiating event typically heralds rapid reversal of AKI (16th ADQI consensus report of 2017).CKD is classi ed zero to seven stages (stages of 0, 1, 2, 3a, 3b, 4 and 5) according to estimated glomerular ltration rate (eGFR) and kidney damage such as proteinuria (>200 mg/day or protein to creatinine ratio > 200 mg/g creatinine) or albuminuria (urinary albumin excretion ≥ 30 mg/day or albumin to creatinine ratio ≥ 30 mg/g creatinine).eGFR is de ned according to creatinine clearance (CrCl), CockGroft-Gault equation, modi cation of diet in renal disease (MDRD) and chronic kidney disease-epidemiology collaboration (CKD-EPI).CrCl in 24-hr urine collection is expressed using urine creatinine (mg per deciliter or micromole per liter) multiplication by urine volume (milliliter or liter) divided on plasma creatinine (milligram per deciliter or micromole per liter) multiplied 1440 and it s unit is expressed with milliliter per minutes (ml/min).Cockcroft-Gault equation is expressed as CrCl=(140-age)´wt divided on SCr´72, multiplication by 0.85 if female.MDRD equation given by: estimated GFR=175´Standardized SCr -1.154 ´age -0.203 ´1.212 [if black] ´0.742 [if female] where eGFR is expressed as ml/min/1.73m 2 of body surface area and SCr is expressed as mg per dl.The CKD-EPI equation, expressed as a single equation, is eGFR=141´min (Scr¤k,1) a ´ max (Scr¤k,1) -1.209 ´ 0.993 age ´ 1.018 where k is 0.7 for females and 0.9 for males, a is -0.329 for females and 0.411 for males, min indicates the minimum Scr¤k or 1 and max indicates the maximum of Scr¤k or 1. Proteinuria, albumin-to-creatinine ratio (ACR) is greater than 2.5 mg/mmol in men or 3.5 mg/mmol in women, or a protein-to-creatinine ratio (PCR) is greater than 15 mg/mmol is su cient for diagnosis of CKD (random PCR < 15 mg/mmol: normal; 15-49 mg/mmol: trace proteinuria; 50-99 mg/mmol: signi cant proteinuria; 100-300 mg/mmol: high proteinuria; > 300 mg/mmol: nephrotic range proteinuria).Albuminuria may be classi ed as moderately increased albuminuria (3-30 mg/mmol creatinine or severely increased albuminuria (greater than 30 mg/mmol creatinine).The normal PCR in children and adolescent is less than 0.3.In infants and younger children, the PCR is higher with the upper normal limit of 0.5.PCR above 3 is found in patients with nephrotic syndrome.The daily protein excretion rate (PER) can be determined from spot urine PCR, based on sex, age and weight using the following equations: PER (g/m 2 /day)=0.63*(PCR).

De nition of transmission of infection to others
Person-to-person spread is thought to occur mainly via respiratory droplets.CoVid-19 virus RNA has been detected in blood and stool specimens.
Through respiratory droplets generated by sneezing and coughing by infected person, generally when present in close proximity.By manual touching of infected surface (having the SARS-CoV-2 virus from symptomatic or asymptomatic person) and then hand touching the mouth, nose or eyes.
Transmission do not occur through simple air (virus remain contained in sneezing droplets).No vertical mother-to-child transfer in case of pregnant women was seen [3].

De nition of hyperpyrexia
A morning readings > 37.2 o C (98.9 o F) or an afternoon temperature of > 37.7 o C (99.9 o C) would be considered a fever.Rectal temperatures are generally 0.6 o C (1 o F) higher than oral readings.Oral readings are lower probably because of mouth breathing, which is particularly important in patients with respiratory infections and rapid breathing.Tympanic membrane temperature readings are close to core temperature.The normal early morning to late afternoon daily increase is typically 0.5 o C (0.9 o C).However, in some individuals recovering from a febrile illness, this daily variation can be as high as 1.0 °C.During a febrile illness, the daily low early morning and high evening temperature difference is maintained but shifted upwards to higher levels.In menstruating women, the morning temperature is generally lower during the two weeks prior to ovulation, rising by about 0.6°C (1.0°F) with ovulation and remaining at that level until menses occur.Seasonal variation in body temperature has been described, but this may re ect a metabolic change and is not a common observation.Elevation in body temperature occurs during the postprandial state, but this is not fever.Pregnancy and endocrinologic dysfunction also affect body temperature.The daily temperature variation appears to be xed in early childhood.On the other hand, it is well established that the ability to develop fever in older adults is impaired and that baseline temperature in older adults is lower than in younger adults.Thus, older adult patients with severe infections may only display a modest fever [4].

De nition of tachycardia and tachypnea
Equal or elevated heart rate of 100 beat per minute is de ned as tachycardia and increased respiratory rate > 20 breaths per minute is de ned as tachypnea.

De nition of Hypertension
Based on the most recent American Heart Association/American College of Cardiology (AHA/ACC) guidelines, an o ce BP of less than 120/80 is considered as normal and o ce BPs in the range 120 to < 130/80 mmHg are considered to be elevated.An o ce BP of 140/90 mmHg is thought to correlate with an ambulatory blood pressure monitoring (ABPM) in 24-hr with average BP of 130/80 mmHg (135/85 mmHg daytime and 120/70 mmHg nighttime mean BPs) and home BP of 135/85 mmHg.Hypertension is de ned as SBP ³ 130 and /or DBP ³ 85 mmHg or under medical treatment for hypertension.

Clinical suspicion or criteria for CoViD-19 diagnosis
Upto now, the possibility of CoVid-19 infection should be considered primarily in patients with fever and/or lower respiratory tract symptoms who reside in or have recently (within the prior 14 days) traveled to areas where community transmission has been reported (e.g.China, South Korea, Italy, Iran, Japan) or have had recent (within the prior 14 days) close contact with a con rmed or suspected cases of COVID-19.The possibility of COVID-19 should also be considered in patients with severe lower respiratory tract illness when an alternative etiology cannot be identi ed though has been no clear contact or exposure with infected patient [4].

De nition of cell lineages in peripheral blood
Leukocytosis is de ned as a total WBC more than two standard deviations above the mean, or a value greater than 11000/microliter in adults.Leukopenia is de ned as a total WBC less than 4400/microliter in peripheral blood.Neutrophilic leukocytosis is de ned as a total WBC above 11000/microL along with an absolute neutrophil count (ANC) more than two standard deviations above the mean (greater than 7700/microL in adults).Moreover, Neutrophilic leukocytosis is de ned as neutrophil count more or equal than 75% in peripheral blood system (60 to 70% as normal percent).
Lymphocytic leukocytosis is de ned as a total WBC in excess of 11,000/microL primarily due to an absolute lymphocyte count in excess of 4800/microL.Normal ndings of this blood component is de ned 20 to 40% and lymphocytosis is considered above 40%.Other references de nes this range 18-65% for 15 days-5 months, 18-60% (6-23 months), 13-55% (2-5 years), 13-50% (6-11years), 13-45% (12-17 years) and 17-47% (> 17 years).Proportions of lymphocytes below reference range is de ned relative lymphocytopenia.An ANC <1500/microL (<1.5 x 10 9 /L) is the generally accepted de nition of neutropenia for adults, as well as the threshold for neutrophil toxicity and infectious risk following chemotherapy.The normal range for the ANC varies somewhat with age.The lower limit of normal is 5000/microL (5.0×10 9 /L) for the rst week of life, then falls to 1000/microL (1.0×10 9 /L) between two weeks and one year of age.Neutropenia is often categorized as mild, moderate or severe, based upon the level of ANC.Mild neutropenia corresponds to an absolute neutrophil count between 1000 and 1500/microL, moderate between 500 and 1000/microL, and severe with less than 500/microL.
Lymphocytosis is de ned as an ALC > 4000 cells /microliter (also expressed as >4000/mm 3 or >4.0 x 10 9 /L).Lymphocytopenia has been variously de ned in older children and adults as an ALC <1000 or <1500 cells/microL.Circulating blood lymphocytes include populations of T cells, B cells, and natural killer (NK) cells.Their normal relative proportions in the blood are: T cells (eg, CD3 + cells) -60 to 80 percent, B cells (eg, CD20 + cells) -10 to 20 percent, NK cells (eg, CD56 + cells) -5 to 10 percent.The normal relative proportions of T cell subtypes in the blood are: Helper/inducer T cells (ie, CD4 + T cells) -60 to 70 percent, Suppressor/cytotoxic T cells (ie, CD8 + T cells) -30 to 40 percent.Alanine aminotransferase (ALT) > 29 to 33 IU/L in male and > 19 to 25 IU/L in female is de ned abnormal serum aminotransferase levels.An aspartate aminotransferase (AST) cut off of 10 to 40 IU/L in for men and 9 to 32 IU/L in women is considered abnormal value.The normal range of lactate dehydrogenase (LDH) is between 140 to 280 U/l.Normal serum albumin is de ned 3.5-5.5 g/dl.Procalcitonine is a biologic marker that are sometimes used for distinguish between bacterial and nonbacterial causes of pneumonia.PCT is a peptide precursor of calcitonin that is released by paranchymal cells in response to bacterial toxins.It increases in bacterial infections and down-regulated in viral infections.It measures by kryptor assay and the immunoluminometric (LUMI) assay.Normal value for procalcitonine in males is ≤19 pg/mL or ≤19 ng/L [international system of units (SI units)] and < 0.5 ng/ml.Amounts of less than 0.1 microgram per liter (mcg/l) levels indicate nonantibiotic need and plasma levels above 0.25 mcg/l needs to antibiotic therapy.The reference range for C-reactive protein (CRP) is < 0.3 mg/dl or < 3mg/l and for high-sensitivity CRP (hs-CRP) is < 3 mg/l.Normal value for cytokine interleukin-2 receptor antagonist (IL-2Ra) level [cluster of differentiation (CD-25)] is 175.3 -858.2 pg/mL and for IL-1b is 0.16-10 pg/ml.Cytokine IL-10 level in ages of 1 to 6 years is assessed 11.4 (9.5-12.8),age groups of 7 to 17 years is assessed 11.3 (8.9-13.7)and age groups of ³ 18 years is assessed 12.6 (8.5-16.7)pg/ml.Cytokine IL-8 level in ages of 1 to 6 years is assessed 30.9 (23.7-32), age groups of 7 to 17 years is assessed 32.6 (28.2-39) and age groups of ³ 18 years is assessed 29.3 (24.4-35.9)pg/ml.level.Normal value for tumor necrosis factor-alpha (TNF-a) is 23-1500 pg/ml.The reference range of cytokine IL-6 for a healthy population is less than 17.4 pg/ml (0-5.9).Normal value for d-dimer is < 500 ng/ml or mcg/l (mg/l), £ 0.49 mg/l in healthy persons.Normal value for brinogen level in adult is 200-400 mg/dL or 2-4 g/L (SI units

Discussion
Coronavirus belong to a big family of viruses that cause a wide range of diseases mainly related to respiratory system and infection may vary from common cold to more severe respiratory diseases.This virus may cause infection in other systems such as kidney, heart, brain and even cause multiorgan failure and culminate to death.Several factors can differentiate between viral and bacterial infections.In patients with lower respiratory tract infection, procalcitonine can serve as a helpful adjunct for guiding antibiotic therapy and resolving diagnostic uncertainty [4].PCT is a marker for bacterial infection which induced by bacteriotoxin but suppressed by interferon.In this research, it was measured in nine of sixty-eight patients (9/68, 13.2%) that was elevated in 7.3% (5/68) cases but was declined in one of sixty-eight cases.Of course, It should be talked that PCT in two of sixty-eight patients was be measured (2/68, 2.9%) and mortality was not seen in those cases.The pathogenesis of SARS is unknown but some reports believe that cytokine storm syndrome or cytokine release syndrome involves in its pathogenesis.These proin ammatory cytokines and chemokines include IL-6, TNFa, IL-1, IL-12, IL-8, interferon gamma.In CoViD-19, IL-2, IL-7, IL-6, IL-10, interferon gamma inducible protein 10 (IP10), monocyte chemoattractant protein (MCP1), macrophage in ammatory protein 1A and TNF-a are increased highly in serum levels of patients.Some are in belief that proin ammatory cytokines increase in proportional with disease severity and IL-6 is an important key cytokine in this disease.Acute phase reactants in covid-19 nephropathy needs to speci c consideration.Classi cation of acute phase reactants is dependent on the change in acute phase proteins (APPs) concentration.A 10-100-fold elevation is considered major; a 2-10-fold elevation is considered moderate; and a less than 2-fold elevation is considered minor.The APPs that elevated in major APRs include CRP and serum amyloid (SA); the APPs that elevated in a moderate APR include α1-acid glycoprotein (AGP); and the APPs that elevated in a minor APR include brinogen, haptoglobin (Hp) and ceruloplasmin (Cp).APRs, acute phase reactants; AAT, a1-antitrypsin; AGP,a1-acid glycoprotein; Cp, ceruloplasmin; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GM-CSF, granulocyte-macrophage colony stimulating factor; Hp, haptoglobin; hs-CRP, high sensitive C-reactive protein; Lf, lactoferrin; IL-1RAs, interleukin-1 receptor antagonists; IL-1 BP, interleukin-1 binding protein; IL-1Rs, interleukin-1 receptors; IL-1BP, interleukin-1 binding protein; IL-2Rs, interleukin-2 receptors; IFN-a, interferon-alpha; MIF-1, macrophage inflammatory protein-1; Nl, normal; SA, serum amyloid A; TNF-a, tumor necrosis factor-a; TNF-a BP, tumor necrosis factor-a binding factor.
).Normal serum creatin phosphokinase (CPK) is de ned in amounts of 55-177 units/l.In other references normal CPK is considered 21-232 IU/l in male adults and in female adults this amount is 21-215 IU/l.Normal serum troponin I is < 0.04 ng/ml and probable heart attack is de ned > 0.4 ng/ml.Normal erythrocyte sedimentation rate (ESR) in male and female is de ned based on following formula: age/2 in male and age +10/2 in female.Elevated ESR was seen in eight of sixty-eight patients (8/68, 11.7%) with mean average of in covid-19 nephropathy.The normal ferritin concentration ranges from 40 to 200 ng/ml (mcg/l).Normal serum sodium is 135-145 mEq/l.Resting arterial oxygen saturation (SaO 2 ) ≤ 95 percent or exercise desaturation ≥ 5 percent is considered abnormal.De nition of positive test for CoViD-19 infectionPatients who meet the clinical criteria in above-mentioned should undergo testing for SARS-CoV-2 infection.Specimens can be collected from the upper respiratory tract (nasopharyngeal and oropharyngeal swab) and if possible the lower respiratory tract (sputum, tracheal aspirate, or bronchoalveolar lavage).Induction of sputum is not indicated.Additional specimens (e.g.stool, urine) can be collected.SARS-CoV-2 is detected by polymerase chain reaction (PCR).A positive test for SARS-CoV-2 con rms the diagnosis of COVID-19.If initial testing is negative but the suspicion for COVID-19 infection remains, the world health organization (WHO) recommends resampling and testing from multiple respiratory tract sites.Negative RT-PCR and speci ty of this assay is 87.3 and 100%, respectively.Serology may have an important role in diagnosing acute and past SARS infection[5].Assessment of risk of bias and quality in included articlesCase reports were analyzed using criteria developed by the Joanna Briggs Institute Critical Appraisal tool for case reports that has different assessment tools for each study design in question.The evaluation tool has 8 items for case reports.Statistical analysisForty-three published articles (68 case reports or participants) were considered for inclusion in this research.Study characteristicsStudy designRandomized data were planned with systematic review and meta-analysis design in this retrospective study and those articles were collected via nonrandomized method.Sample sizesSample sizes of 68 patients or participants were considered in this study.SettingParticipants were referred to emergency room or local hospital in this research.ParticipantsAll patients included in this study had kidney diseases in relation with clinical, laboratory and radiologic features that had positive or negative test for CoViD-19 infection.The patients who had symptoms, signs, laboratory and radiologic characteristics of covid-19 nephropathy and elevated serum creatinine levels or decreased eGFR.Laboratory test for covid-19 included nucleic acid testing for RNA antigen of virus from upper/lower respiratory tract, blood, stool, urine, dialysate uid and tissue.Among screened 1391 full-text articles obtained in this research paper, 1182 articles were excluded due to unrelated subject, review articles and other studies.Then 202 full-text articles were eligible and 159 articles were excluded due to not case report (n=159).Finally 43 published articles were included in this study.These 43 articles included 68 case reports that were examined 68 patients with clinical, laboratory and radiologic presentations of CoViD-19 infection and decreased eGFR with or without positive test for CoViD-19 in sputum, stool, urine, peritoneal dialysis uid and tissue biopsyproven specimens who had renal dysfunction were considered for qualitative and quantitative synthesis in this research [Fig.1].Fifty of sixty-eight were male (50/68, 73.5%) and eighteen of those belonged to female sex (18/68, 26.4%).Twenty-three of sixty-eight patients (23/68, 33.8%) were from Wuhan province of Laboratory data There were leukopenia in ten of sixty-eight patients (10/68, 14.7%) with mean±SD of 3256±712.2/ml,leukocytosis in ve of sixty-eight patients (5/68, 7.3%) with mean±SD of 15997±3350/ml and normal leukocytes in twenty-six of sixty-eight patients (26/68, 38.2%) that quantitated amount was not mentioned in one patient in this article.The mean average of normal leukocytes was assessed 7391.6±1849.2/ml in CoViD-19 nephropathy.There were neutrophilia (count) in four of sixty-eight patients (4/68, 5.8%) and mean average of 13243±3767/ml.Neutropenia was seen in one of sixty-eight patients (1/68, 1.4%).Normal neutrophil count was seen in twelve of sixty-eight patients (12/68, 17.6%) in peripheral blood of CoViD-19 nephropathy that quantitated amount was not mentioned in one patient in this article.The mean average of normal neutrophil count in eleven patients was assessed 5016±1242/ml.Normal ALC was seen in eleven of sixty-eight patients (11/68, 16.1%) that quantitative amount were not mentioned in two patients in article.The mean average of normal lymphocyte count was assessed 1805±969/ml.With consideration of normal peripheral lymphocytes about 30 to 40 percent in the circulating white cells, lymphopenia was seen in thirty-one of sixty-eight patients (31/68, 45.5%).Furthermore, quantitative amount was not mentioned in one patient and mean average of it was assessed of 584.6±226.1/ml.Lymphocytosis was not seen in any of patients with CoViD-19 nephropathy.Neutrophilia as percentage was seen in ve of sixty-eight (5/68, 7.3%) patients with mean average of 84.25±5.56/ml[Fig.4].Elevated CRP with unit of mg/l were seen in thirty-four of sixty-eight patients (34/68, 50%) with mean average of 79.16±87.47mg/landtwelve of sixty-eight patients (12/68, 17.6%) using unit of mg/dl with mean average of 22.30±39.38mg/dl in CoViD-19 nephropathy.There were hypoalbuminemia in six of sixty-eight Mean±SD of elevated SCr in these patients was assessed 2.44± 1.28 mg/dl.eGFRusingCrwasmeasured in twenty-seven of sixty-eight patients (27/68, 39.7%) that there was anuria in two patients and Mean±SD of eGFR was assessed 45.97±15.12ml/min/1.73m 2 .Four of sixty-eight patients (4/68, 5.8%) developed proteinuria in spot urinary protein to creatinine ratio (UPCR) sample and timed urine collection with mean average of 4.89±3.87g/gCrand2.34±2.92gr/24hr,respectively.Moreover, one patient had two plus proteinuria in baseline urine analyses in this research (1/68, 1.4%).There was anemia in ten of sixty-eight of patients (10/68, 14.7%) with mean average of 9.48±1.8g/dl in CoViD-19 nephropathy.There were thrombocytopenia in seven of sixty-eight patients (7/68, 10.2%) that quantitative amount in one patient was not characterized in CoViD-19 nephropathy.The mean average of thrombocytopenia in six patients was assessed 102400±40636.2/ml.Elevated brinogen was seen in seven of sixty-eight patients (7/68, 10.2%) and mean average of 682.3±168 mg/dl in covid-19 nephropathy.There were elevated serum CPK in ve of sixty-eight patients (5/68, 7.3%) with mean average of 10990.ImagingThere were abnormal chest x-ray (CXR) in twenty-eight of sixty-eight patients (28/68, 41.1%) with CoViD-19 nephropathy.Bilateral lung in ltration was seen in nineteen of sixty-eight patients (19/68, 27.9%) and one of sixty-eight patients (1/68, 1.4%) with unilateral lung in ltration.Unilateral pleural effusion was observed in three of sixty-eight patients (3/68, 4.4%) and bilateral pleural effusion in two of sixty-eight patients (2/68, 2.9%).There were nineteen of sixty-eight pulmonary lesions (19/68, 27.9%) in chest scan.These lesions in the lung include multiple or patchy opacities.Bilateral lung opacities, ground-glass, air bronchogram, nodular opacities as focal or diffuse or multiple were seen in chest CT scan.Abnormal transthoracic echocardiography (TTE) was seen in four of sixty-eight patients (4/68, 5.8%) with covid-19 nephropathy.Renal ultrasound performed in two of sixty-eight patients (2/68, 2.9%) with covid-19 nephropathy [Supplementary Table6].TreatmentDrugs for therapeutic purposes of covid-19 nephropathy include entry inhibitors, replication inhibitors (Remdesivir), protease inhibitors (lopinavir/ritonavir), heterocyclic antivirals (chloroquine), nanodelivery drug systems, biological therapeutics and herbal drugs.Oxygen therapy was used in thirty-two of sixty-eight patients (32/68, 47%) with CoViD-19 nephropathy.Antibacterial therapies include moxi oxacin, cipro oxacin,   linezolid, Ceftaruline, meropenem, ceftriaxone, vancomycin, azithromycin, ceftazidime, cefepime, cefuroxime, amoxicillin,.Anti-hypertensive agents include losartan, lamipril, atenolol, nifedipine, olmesarten, hydralazine, clonidine, amlodipine, valsartan, lisinopril.Diuretics include furosemide, amiloride, sprinolactone, hydrochlorothiazide, immunosuppressive patients on continuous venovenous hemodia ltration (CVVHDF) (4/68, 5.8%), three patients on chronic renal replacement therapy (CRRT) (3/68, 4.4%), one patient on continuous venovenous hemo ltration (CVVH) and hemoperfusion (1/68, 1.4%), three patients on RRT 3/68, 4.4%), six patients on ECMO (6/68, 8.8%) and there were sixteen patients of KRTs (16/68, 23.5%).There was allogenic bone marrow (BM) transplantation in one of sixty-eight patients with covid-19 nephropathy (1/68, 1.4%).Thirteen of sixty-seven patients (13/68, 19.1%) underwent ventilator/respirator [Supplementary Table 7].Follow-up in with covid-19 nephropathy There were testing in fteen of sixty-eight patients (15/68, 22%) with covid-19 nephropathy during follow up (f/u).Positive CoViD-19 testing found in two of sixty-eight patients (2/68, 2.9%) with CoViD-19 nephropathy.There were elevated blood urea nitrogen (Bun) in one of sixty-eight patients (1Outcomes end-points was ICU admission in ten of sixty-eight patients (10/68, 14.7%) with covid-19 nephropathy.There was need to mechanical ventilation in thirteen of sixty-eight patients (13/68, 19.1%) with covid-19 nephropathy.Fifteen of sixty-eight patients (15/68, 22%) died during hospital course or post-discharge.There were AKI in four of sixty-eight patients (4/68, 5.8%) with covid-19 nephropathy and AKD found in fourteen of sixty-eight patients (14/68, 20.5%) with covid-19 nephropathy during follow up.Median and interquartile range of SCr during follow up were assessed 1.
There are 8 proteins which are overexpressed in APRs denoted as 'positive' APPs, including Hp, SA, brinogen, Cp, AGP, α-1 antitrypsin (AAT), lactoferrin (Lf) and CRP.Similarly, there are a number of 'negative' APPs the expression levels of which are reduced, including albumin, transferrin and transthyretin.The APP is elicited by cytokines, including those functioning as positive and negative growth factors and cytokines with proin ammatory or anti-in ammatory activity.Positive Cytokines involved in the anti-in ammatory response include: IL-1 receptor antagonists; soluble IL-1 receptors; IL-1 binding protein; and TNF-α binding protein.Moreover, ESR and ferritin increase in these patients.Covid-19 with hyperin ammatory pulmonary symptoms is associated with a cytokine storm involving interleukins and chemokine dysregulation.Of important cytokines is interleukin-6[49].One of achievements of this research is effect of elevated IL-6 on decreased eGFR and this effect on kidney failure can be substantial.In relation to this result, tocilizumab is recommended in severely infected cases with elevated IL-6 in serum.In our research, tocilizumab has been used in 13.2% (9/68) of patients and two of sixty-eight patients (2/68, 2.9%) were expired.As such we know ceruloplasmin is one of positive APRs and associated cytokines include TNF-a, IL-1b and IFN-1.Other point in this research is usage of interferons that were used in six of sixty-eight patients (6/68, 8.8%) and responsed to it in 7.3% cases (5/68).Angiotensin converting enzyme -2 (ACE2) is acellular receptor for SARS-CoV and SARS-CoV-2.ACE2 shares some homology with ACE but is not inhibited by angiotensin converting enzyme inhibitors (ACEIs).ACE2 is expressed in lung, heart, kidney and intestine as SARS-CoV-1, it may be hypothesized that chloroquine also interferes with zoonotic infectious disease, belong to Nidovirales order, coronaviridae large family and coronavirinae subfamily.Preliminarily, CoVs are able to infect mammals and birds by causing various lethal diseases.Notably, following some genetic mutation, this virus has potential to lead in respiratory system from upper respiratory tract by resembling simple cold symptoms to lower respiratory tract such as bronchitis and pneumonia as well as SARS that both of these infections arising from human CoVs.In our research, there was not correlation between lymphocytopenia and elevated serum creatinine.Moreover, effect size of elevated IL-6 on decreased eGFR was medium.Relative risk and odds ratio of covid-19 in emerging acute kidney disease in covid-19 nephropathy was assessed 0.57 and 0.4, respectively.Future research is needed for investigating more unknown ndings about ACE2 receptor glycosylation thus preventing SARS-CoV-2 binding to target cells.Different therapeutic modalities have been used in covid-19 nephropathy sofar.A recently case report described the bene cial effect of thalidomide (100 mg daily) plus low dose glucocorticoids[50].Previously, Amirshahrokhi in an experimental study in mice showed thalidomide ameliorated the histological and biochemical lung alterations induced by parquet (PQ).Thalidomide decreased production of in ammatory and brogenic cytokine TNF-a, IL-1b, IL-6 and transforming growth factor-beta1 (TGF-b1).Moreover, myeloperoxidase (MPO) activity, nitric oxide (NO) and hydroxyproline content in lung tissue were declined[51].Our study revealed the most common Declarations Acknowledgement: The author to wish thanks National University of Tehran Medical Sciences, College of Medicine and Imam Khomeini Hospital Complex.Moreover, the author offers this paper to all of health martyrs in world.