Clinical trial NCT04530448
Conditions: COVID Coronavirus Coronavirus Infection AKI Acute Kidney Injury
Keywords: Acute Kidney Injury AKI COVID-19 Coronavirus Sodium Bicarbonate
Sponsor: West Virginia University
Start date: 2020-10-05; Completion date: 2021-07-15
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Our overarching goal is to improve the outcomes of critically ill COVID-19 patients with or at risk for development of acute kidney injury (AKI). The objective of this study is to determine the role of a protocol to manage urine alkalization using a simple medication that has been used for a very long time, is safe, and without significant side-effects. We aim to determine the feasibility and safety of a urine alkalinization protocol for the prevention of AKI in patients testing positive for COVID-19.

Detailed description:
Emerging evidence suggests that acute kidney injury (AKI) secondary to COVID-19 (COV-AKI) might result from direct infection of renal tubule epithelial cells (RTEC). A variety of epithelial cells express the ACE2 receptor which contains the receptor-binding domain (RBD) used by SARS-CoV-1 and SARS-CoV-2 to enter the cells. While direct infection of RTEC has not yet been proven data from multiple laboratories show virus in the kidney. It is this direct viral involvement of the RTEC that this proposal seeks to address.

One relatively simple approach would be to perturb the ability of the RBD to bind to its cellular (hACE2) receptor. Changes in pH may cause each amino acid residue, in the RBD, to assume a slightly different 'microscopic' conformation-dependent pKa value. Urine pH is normally 5.5- 6.5 (not too dissimilar to alveolar fluid-6.4-6.86) and can be easily and safely manipulated. In fact, urine alkalinization protocols have been used for decades to reduce renal toxicity from various compounds (especially chemotherapy) and are recommended by US and European toxicology societies. Here, the strategy will be deployed not for ion trapping but to inhibit the virus from infecting RTEC. Alkalinizing the urine using IV sodium-bicarbonate solution to pH of 7.5 or more can be easily and safely achieved.

While severe AKI does not appear to be a major part of the SARS-CoV-2 syndrome for most patients, when severe AKI does occur, mortality is very high and preventing early AKI may reduce AKI severity as the disease progresses.

Arms: arm 1: Standard of Care treatment arm 2: Sodium bicarbonate 225 mEq (225 mL of an 8.4% solution) intravenously over 1 hour. Sodium bicarbonate 8.4% solution should not exceed 900 ml (4 boluses) in 24 hours.
Interventions: intervention 1: Sodium bicarbonate intervention 2: Standard of Care
Intervention descriptions: intervention 1: Sodium bicarbonate 225 mEq (225 mL of an 8.4% solution) intravenously over 1 hour. Sodium bicarbonate 8.4% solution should not exceed 900 ml (4 boluses) in 24 hours. intervention 2: Standard of Care treatment

Protocol documents:
Prot_SAP_000.pdf: 
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Pop-Up COVID-19 Grant Application 
West Virginia Clinical and Translational Science Institute 
 
 
Principal Investigator’s Information 
 
PI 
Name 
Ankit Sakhuja 
Title 
Assistant Professor of Medicine 
College 
School of Medicine 
Department/ Division 
Department of Cardiovascular and Thoracic Surgery 
Email Address 
Ankit.sakhuja@hsc.wvu.edu 
Phone 
304-598-4651 
Co-PI 
Name 
Paul J McCarthy 
Title 
Assistant Professor of Medicine 
College 
School of Medicine 
Department/ Division 
Department of Cardiovascular and Thoracic Surgery 
Email Address 
Paul.McCarthy@hsc.wvu.edu 
Phone 
304-598-4651 
Co-I’s 
Name 
Vinay Badhwar 
Name 
Galen Kabulski 
Name 
Richard Goldberg (Added as per COE requirement) 
Name 
Sarah Hadique 
Name 
John Kellum 
 
 
TITLE OF APPLICATION: Coronavirus Induced Acute Kidney Injury: Prevention using Urine 
Alkalinization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROJECT ABSTRACT (30 Lines or Less) 
 
 
Emerging evidence suggests that acute kidney injury (AKI) secondary to COVID-19 (COV-AKI) 
might result from direct infection of renal tubule epithelial cells (RTEC). A variety of epithelial 
cells express the ACE2 receptor which contains the receptor-binding domain (RBD) used by 
SARS-CoV-1 and SARS-CoV-2 to enter the cells. While direct infection of RTEC has not yet 
been proven data from multiple laboratories show virus in the kidney. It is this direct viral 
involvement of the RTEC that this proposal seeks to address. 
 
One relatively simple approach would be to perturb the ability of the RBD to bind to its cellular 
(hACE2) receptor. Changes in pH may cause each amino acid residue, in the RBD, to assume 
a slightly different ‘microscopic’ conformation-dependent pKa value. Urine pH is normally 5.5- 
6.5 (not too dissimilar to alveolar fluid—6.4-6.86) and can be easily and safely manipulated. In 
fact, urine alkalinization protocols have been used for decades to reduce renal toxicity from 
various compounds (especially chemotherapy) and are recommended by US and European 
toxicology societies. Here, the strategy will be deployed not for ion trapping but to inhibit the 
virus from infecting RTEC. Alkalinizing the urine using IV sodium-bicarbonate solution to pH of 
7.5 or more can be easily and safely achieved. 
 
While severe AKI does not appear to be a major part of the SARS-CoV-2 syndrome for most 
patients, when severe AKI does occur, mortality is very high and preventing early AKI may 
reduce AKI severity as the disease progresses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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A. SPECIFIC AIMS (1 page max) 
 
COronaVirus Infectious Disease 2019 (COVID-19), since its initial discovery in December 2019 
has affected millions of lives across the world. As of this writing it has infected over 3 million 
people across the world with almost a third of those in the United States (US). It has so far 
claimed over 200,000 lives worldwide with over a quarter of those in the US. 
COVID-19 is caused by Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV2), a β- 
coronavirus. It most commonly affects lungs leading to acute respiratory distress syndrome, but 
involvement of other organs leading to cardiomyoapathies, acute kidney injury (AKI) and gastro- 
intestinal systems has been frequently described. AKI, a sudden dysfunction of kidneys, is 
common among critically ill patients and is associated with high mortality, morbidity and 
increase in healthcare costs. It is seen in 15-25% patients with COVID-19. The treatment relies 
on prevention of progression of AKI and management of its complications. Initiation of dialysis 
therapy is needed in 6-13% of critically ill patients with AKI and is associated with very high 
mortality. As such there is a critical need to identify and develop therapies to delay the 
progression of AKI in these patients. 
Our overarching goal is to improve the outcomes of critically ill patients with or at risk for 
development of AKI. The objective of this applications is to determine the role of urine 
alkalization in prevention of development and progression of AKI in critically ill patients with 
COVID-19. A recent study has shown invasion of renal tubular epithelial cells by SARS-CoV2 
virus. Urinary alkalinization, that has been used in millions of patients to reduce renal toxicity 
from various nephrotoxins including chemotherapeutic agents and drug overdoses (e.g. aspirin), 
will lead to a conformational change in the amino acids of the receptor binding domain of 
coronavirus leading to decreased binding affinity of the virus to its receptor on renal tubular 
epithelial cells. We hypothesize that alkalization of urine is safe and effective to prevent 
development of AKI in patients with COVID-19. To achieve our objective we are proposing to 
conduct a pragmatic randomized clinical trial of 40 patients testing positive for COVID-19 with 
the objective of preventing the development of moderate-severe AKI. We have two specific 
aims. 
 
Aim 1: To determine the feasibility and safety of a pragmatic urine alkalinization protocol 
for the prevention of AKI in patients testing positive for COVID-19. Primary outcome will be 
the proportion of patients treated who achieve >50% of urine measurements above pH 7.0 over 
the duration of intervention. Other outcomes will include protocol adherence and provider 
acceptance. 
Aim 2: To determine the effectiveness of urine alkalinization for prevention of AKI in 
patients testing positive for COVID-19. Primary outcome will be the number of days alive and 
free of stage 2-3 AKI (up to 28) in each group. Secondary endpoints will include the proportion 
of patients developing stage 2-3 AKI (or stage 3 if already at stage 2 at enrollment); ventilator- 
free days to 28 and hospital-free days to 60. 
Completion of this study will provide clinically relevant information regarding the role of urine 
alkalinization in prevention of AKI associated with COVID-19. This will have wide ranging 
implications for patients with COVID-19. Dr. John Kellum, Professor and Vice Chair for 
Research in the Department of Critical Care Medicine at the University of Pittsburgh, a co-I on 
this application and my co-mentor for the WVCTSI research scholar application is also in the 
process of conducting this study at the University of Pittsburgh. At the completion of this study, 
the results from both centers (WVU and UPitt) will then be pooled and changes in AKI rates, 
and survival will be examined among patients with COVID-19. 
 
 
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B. RESEARCH STRATEGY (5 pages max) 
 
1. Background 
 
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is rapidly spreading around 
the world. The current outbreak of infections with SARS-CoV-2 is termed Coronavirus Disease 
2019 (COVID-19). Two other coronavirus infections, SARS in 2002-2003 and Middle East 
Respiratory Syndrome (MERS) in 2012, both caused severe respiratory syndrome in humans. 
All 3 of these emerging infectious diseases are caused by β-coronaviruses. COVID-19, declared 
a pandemic by the World Health Organization on Mar 11, 2020, is associated with high mortality 
in patients admitted to intensive care units (ICUs) [1]. Though COVID-19 primarily affects lungs 
leading to Acute Respiratory Distress Syndrome (ARDS), other life-threatening acute organ 
dysfunctions such as acute kidney injury (AKI) and cardiomyopathies are also commonly 
described. 
AKI, defined as a sudden decrease in function and damage to kidneys is common among 
critically ill patients. The creatinine based Kidney Disease Improving Global Outcomes (KDIGO) 
criteria define AKI as an increase in serum creatinine by 1.5 times the baseline creatinine of by 
≥ 0.3mg/dL[2]. The incidence of AKI at 2.1 per 1000 population is similar to that of heart attacks 
[3]. It is seen in 10-15% of all hospitalized patients but has been described in over 50% of 
critically ill patients [4, 5]. It has been described to be present among 15-25% patients with 
COVID-19 [6, 7]. 
AKI is not only common but is associated with 3-4 times higher mortality [8, 9], development of 
chronic kidney disease [10], end stage renal disease [11] and increase in healthcare 
expenditure [12]. There are no definitive therapies for AKI and treatment primarily rests on 
prevention of progression of AKI and management of its complications such as hyperkalemia, 
acidosis and volume overload. Approximately 6-13% of critically ill patients develop severe AKI 
that requires life-saving dialysis therapy [5, 13] but dialysis itself is associated with high 
mortality[13] and life-threatening complications such as infections. Therefore there is a great 
interest in developing therapies and treatment approaches that can prevent AKI in critically ill 
patients. 
 
2. Hypothesis 
 
We hypothesize that alkalization of urine is safe and effective to prevent development of AKI in 
patients with COVID-19 
 
 
3. Significance 
 
Although COVID-19 primarily affects the lungs and may cause severe hypoxemia, other organs 
including the GI tract, heart and kidney are affected. Acute kidney injury secondary to COVID-19 
(COV-AKI) is reported to occur in about 15-25% of patients hospitalized with COVID-19 
infection.[6, 7] However, AKI was much more common in non-survivors (>50%). The majority of 
AKI cases are mild to moderate with renal replacement requirement in about 25% of AKI cases. 
But with COVID-19 taking the form of a pandemic, this has translated into thousands of patients 
needing dialysis. There are already reports of hospitals running out of dialysis machines to 
provide life-saving therapy critical for COVID-19 patients with AKI. As such there is a critical 
need to identify therapies that can delay the development or progression of AKI in these 
patients. Although kidney failure appears to occur late in the course, patients may begin to 
 
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develop AKI within the first 3 days of hospitalization.[6] Thus, there may be a long window for 
treatment and prevention of early AKI that may decrease renal failure. 
Similar to AKI in other settings,[14] COV-AKI is likely to be of variable etiology. Most patients 
present with single-organ failure (severe hypoxemia). Thus, remote organ injury, including AKI 
can simply be a consequence of critical hypoxia. Late cardiac involvement, reported in some 
series, may also cause cardio-renal syndrome. Furthermore, while typical cases do not appear 
to cause significant hyperinflammation, a few patients develop a microphage-activation 
syndrome-like phenotype with cytokine storm and high plasma ferritin. This may be the cause of 
severe AKI in this subgroup. However, AKI might also result from direct infection of renal 
tubule epithelial cells (RTEC). A variety of epithelial cells express the ACE2 receptor and this 
receptor is used by β-coronaviruses to enter the cells.[15, 16] An autopsy study of 26 COVID-19 
patients recently confirmed the invasion of RTECs by SARS-CoV2 with COVID-19[17]. 
It is this direct viral involvement of the RTEC that this proposal seeks to address. One relatively 
obvious solution would be to block the ACE2 receptor pharmacologically and hence prevent the 
virus from entering the cells. While this could be an attractive therapy, ACE2 activity has been 
shown to be protective in lung injury[18] and no renal specific ACE2r antagonists are available 
to study. An alternative approach would be to perturb the ability of the receptor-binding domain 
(RBD) of β-coronaviruses[15] to bind to its cellular (hACE2) receptor. Changes in pH[19] may 
cause each amino acid residue in the RBD to assume a slightly different ‘microscopic’ 
conformation-dependent pKa value. Conformational change may alter the affinity of the RBD for 
its receptor and this may not jeopardize the function of the enzyme. The pH-induced potential 
for minor conformational change and/or steric hindrance[20] is possible due to the bulky 
phenylalanine residue in position 486 (F486 in h2019-nCoV RBD6) and in positions 442 and 
472 (Figure 1).[21] 
 
 
 
 
Figure 1. Structure of hACE2 receptor and the SARS-CoV RBD.[22] 
 
 
4. Innovation 
Thus, the innovative idea of simply drinking sodium bicarbonate solutions to induce minor 
changes in blood pH has been proposed.[21] This idea suffers from two major limitations. First, 
the pH change required to have significant effect on disrupting the RBD is likely to be too great 
to safely achieve in blood—a rule of thumb is at least 1 pH unit.[23] Second, even if this could 
be achieved the expression of ACEr is on the apical (lumen) surface of epithelial cells not the 
basolateral (plasma) side.[16] However, neither of these are problems for the kidney. Urine pH 
 
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is normally 5.5-6.5 (not too dissimilar to alveolar fluid—6.4-6.8[24]) and can be easily and safely 
manipulated. In fact, urine alkalization protocols have been used for decades to reduce renal 
toxicity from various compounds (especially chemotherapy) and are recommended by US and 
European toxicology societies.[25] Here, the strategy will be deployed not for ion trapping but to 
inhibit the virus from infecting RTEC. Alkalinizing the urine using IV sodium-bicarbonate solution 
to pH of 7.5 or more can be easily and safely achieved. Acetazolamide can also be added if 
systemic alkalemia is an issue.[25] An additional advantage of this approach is that it is unlikely 
to interfere with other interventions that can be studied in these patients (e.g. steroids) which 
are directed at the lungs. 
 
5. Approach 
We will conduct a pragmatic RCT using alkalinization of urine such that most ICU COVID-19 
positive patients can be enrolled. Both specific aims will be achieved by the conduct of the trial 
yet both are independent. The statistical analysis plan for each aim will detail the specific 
endpoints and hypotheses being testing. 
Trial overview: Study inclusion and exclusion criteria are provided in Table 1. 
Study design: Open-label randomized trial (1:1) comparing urine alkalinization to standard care. 
The study will test both feasibility and safety (aim 1) as well as efficacy (aim 2). 
Study Management: Study personnel will identify patients and obtain video-enabled informed 
consent from patients or legally authorized representatives; collect study data and ensure 
sample collection, processing and storage. The patient’s bedside nurse will perform urine pH 
measurement (dipstick) and deliver the study drug. The study is open-label to facilitate safety 
and allow for any management of complications (e.g. calcium supplementation). 
 
 
Table 1. Inclusion/exclusion Criteria 
Inclusion Criteria 
Exclusion Criteria 
Confirmed COVID-19 + 
Stage 3 AKI by KDIGO criteria 
Admission to ICU or step-down 
units at WVU 
CKD stage 4-5 
Foley catheter* and central line (or 
PICC) in place 
Contraindications to Na bicarbonate 
therapy (e.g. met. alkalosis, severe 
heart failure) 
Age ≥18y 
Urine pH > 7.0 
ECMO Patients 
*Foley Catheter can be removed 72 hours after enrollment if appropriate 
documentation of urine output can be maintained 
 
 
 
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Urine alkalinization may also increase the elimination of certain drugs including 
hydroxychloroquine. We do not intend to exclude patients taking these drugs but it will be 
discussed in the consent form and with the treating physicians. 
Intervention: The intervention is a modification/simplification of a standard protocol used for 
decades for the treatment of various drug toxicities (e.g. salicylate) or to mitigate kidney damage 
from chemotherapy.[25] Simplifications are intended to tailor the intervention to the 
management of COVID-19 patients and reduce or eliminate any additional staff exposure. We 
will continue urine alkalinization for 10 days or until patient is discharged from ICU or step-down 
unit or until the stage 3 AKI or a safety endpoint is reached. Urine pH will be measured at POC 
by dipstick. The major elements of the interventional protocol are shown in Table 2. Note, much 
of the monitoring (e.g. blood gases, calcium) is already performed for routine care. The protocol 
simply ensures that these measurements are timed to maximize patient safety and minimize 
burden on bedside nurses. The protocol has been developed with input from Dr. John Kellum, 
Professor and Vice Chair for Research in the Department of Critical Care Medicine at the 
University of Pittsburgh. 
 
Table 2. Protocol highlights 
Sodium bicarbonate 225 mmol (225 mL of an 8.4% solution) intravenously 
over 1h 
Recheck urine pH (dipstick) in 2-4 hours (from start of infusion) 
Repeat boluses of intravenous sodium bicarbonate to achieve urine pH 
≥7.2 
Monitor urine pH every 2-4 hours until target is reach and then q6-8 hours 
Sodium bicarbonate 8.4% solution should not exceed 900 ml (4 boluses) in 
24h 
Monitor plasma sodium, potassium, calcium every 12 hours and Acid-base 
status at least every 24 hours (Note: Arterial pH should not be > 7.50, or 
venous >7.55) 
Acetazolamide (Diamox) can be administered at physicians’ discretion to 
control systemic alkalinization and to help avoid fluid accumulation. 
Avoid fluid accumulation. If urine output does not increase to compensate 
for the increased fluid (it will in most cases, especially if kidney is 
protected), Lasix or Diamox can be added. 
*If fluid balance cannot be maintained within +1L in 24 hours – protocol will 
be halted and resumed only if either the fluid balance can be correct to 
within +500mL in 24 hours or if the primary team decides that the patient 
has clinically appropriate fluid balance. 
Data 
collection: Information will be collected about patient demographics – date of birth, age, sex, 
race, weight, height, co-morbidities including but not limited to diabetes, hypertension, heart 
failure, coronary artery disease, previous cardiac surgeries, chronic kidney disease, cancers. 
Given the long history and familiarity with urine alkalinization, potential adverse effects (e.g. 
metabolic alkalosis, hypocalcemia) are well known. Data about renal function (creatinine, urine 
output, daily ins and outs), basic metabolic panel, blood gas, home medications, medications 
given during hospital stay and chart review to identify any relevant complications will also be 
performed. The provider survey will be performed using an online survey instrument and a link 
will be emailed to the provider to complete. 
Sample collection: We will collect urine samples (1 before, 1 at 24 hours and 1 at 48 hours) from 
initiation of the protocol. Urine samples will be collected, processed and stored in accordance 
 
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with EH&S requirements for COVID-19 samples. At a later date and using alternative funding, 
we plan to analyze these samples for additional biomarkers either at WVU or at partner 
institution(s) in that study.[26] These biomarkers measure the cellular stress in the kidney[27] 
and will be examined in an ancillary study. The samples will be stored initially at the laboratories 
in WVU and then shipped to partner institution(s) for further testing of urine biomarkers as 
detailed above. 
Statistical analysis: Descriptive statistics will be used for reporting: continuous variables 
expressed as median and interquartile range while categorical variables as frequency and 
percentages. No imputation will be performed and missing data will be treated as missing. 
Aim 1: To determine feasibility and safety of a pragmatic urine alkalinization protocol for the 
prevention of AKI 
Primary feasibility outcome will be the proportion of patients treated who achieve >50% of urine 
measurements pH ≥ 7.2 over the duration of treatment. Following specific adverse events will 
be monitored – hypokalemia (K<3.0meq/L), hypocalcemia (Ca<7.6mg/dL when corrected for 
albumin), Hypernatremia (Na>155meql/L), Volume overload (gaining weight >10% from 
admission weight during the protocol time-period, need for positive pressure ventilation or 
intubation due to volume overload), arrhythmias due to hypokalemia or hypocalcemia. To 
assess safety and feasibility, summary statistics including frequency, mean, standard deviation, 
median and interquartile range will be provided as applicable. Baseline data will be summarized 
comparing treatment groups over time. Chi-square/t-test will be used to compare the difference 
between treatment groups. Mixed model /ANCOVA will be used for repeated measurements 
over time. 
As per the requirements of COE, a Data Safety Monitoring Board (DSMB) has been established 
that includes Dr. Awori J Hayanga, Dr. Chris Cook, Dr. Matthew Ellison and Dr. Lisa Giblin 
Sutton. The DSMB will meet to review any adverse events after 5 and 25 patients have been 
recruited. In addition, as per the requirements of COE, the DSMB will meet to review any 
adverse events after the first 5 patients randomized to the interventional drug (open label arm) 
have been recruited and completed the study. 
 
 
Aim 2: To determine the efficacy of urine alkalinization for prevention of AKI 
Primary efficacy outcome will be the number of days alive and free of stage 2-3 AKI (up to 28) in 
each group. Secondary endpoints will include the proportion of patients developing stage 2-3 
AKI (or stage 3 if already at stage 2 at enrollment); ventilator-free days to 28 and hospital-free 
days to 60. For AKI-free, ventilator-free, and hospital-free days, zero truncated negative 
binomial models will be implemented. 
Severe AKI will be considered as binary outcome. Multivariable logistic regression will be used 
to assess the overall odds associated with treatment adjusted by baseline covariates (age, 
demographics, baseline renal function). Random forest decision tree regression method will be 
implemented to assess patient variable importance towards the outcome. Hazard will be 
assessed using cox proportional hazard model. 
Sample size determination: The study will be powered to achieve a 50% increase in the number 
of days alive and free of stage 2-3 AKI to day 28. We hypothesis an increase from 10 +/- 5 days 
to 15 +/- 5 days. The sample size needed to achieve this difference is 16 patients per group. We 
plan to enroll 20 patients per group for a total sample size of 40 patients. Dr. John Kellum, 
Professor of Critical Care Medicine at the University of Pittsburgh and a co-investigator on this 
application is working towards a similar trial at the University of Pittsburgh (see attached letter of 
 
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support). The results from both these studies will then be pooled and changes in AKI rates, and 
survival will be examined. 
Relevance to the current COVID-19 pandemic 
There are at least four reasons why this study will have an important impact. First, when severe 
AKI does occur, mortality is very high.[6, 7] Preventing early AKI may reduce severe AKI as the 
disease progresses. Second, AKI has considerable effects on the immune system reducing a 
variety of immune functions[28] and hence might contribute to reduced host response. Third, 
this is unlikely to be the last β-coronavirus outbreak and different strains may cause even more 
AKI. Finally, the results of this study would provide critical proof of concept data that could be 
used to design other therapies to reduce viral RBD affinity. For example, alveolar pH could also 
be manipulated. Showing feasibility with this safe and available strategy could be the first step 
toward other related efforts. 
 
 
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Clin Toxicol 2004, 42(1):1-26. 
26. 
Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, Bihorac A, Birkhahn R, 
Cely CM, Chawla LS et al: Discovery and validation of cell cycle arrest biomarkers in 
human acute kidney injury. Critical care 2013, 17(1):R25. 
27. 
Emlet DR, Pastor-Soler N, Marciszyn A, Wen X, Gomez H, Humphries WHt, Morrisroe S, 
Volpe JK, Kellum JA: Insulin-like growth factor binding protein 7 and tissue inhibitor of 
metalloproteinases-2: differential expression and secretion in human kidney tubule 
cells. Am J Physiol Renal Physiol 2017, 312(2):F284-F296. 
 
 
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28. 
Singbartl K, Formeck CL, Kellum JA: Kidney-Immune System Crosstalk in AKI. Seminars 
in nephrology 2019, 39(1):96-106. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 

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Key Information for: 
Coronavirus Induced Acute Kidney Injury: Prevention using Urine Alkalinization 
You are being asked to participate in the research described below. This page provides key information that 
may help you to make this decision; more detailed information can be found after this section. 
Why is this research being done and what is involved? 
The Coronavirus (COVID-19) is impacting the entire world. Since this virus is new, there is not a lot of 
information available for doctors and clinical staff on how the disease behaves, how to treat patients, and the 
outcomes of patients. COVID-19 is known to affect kidney function and cause Acute Kidney Injury (AKI). The 
objective of this study is to determine the role of urine alkalization in the prevention of the development and 
progression of AKI in critically ill patients with COVID-19. Urine alkalization is a process that helps to lower 
high levels of acid in the blood or urine that can be caused by certain medicines or conditions. It has been used 
for a long time in treatment of various drug toxicities. This study hopes to better understand how COVID-19 
impacts the patient’s kidneys. 
Should you choose to participate, you will be randomized to one of the two groups - standard of care 
(control) group or the study (intervention) group. If you are randomized to the study group you will be given an 
intravenous medication called sodium bicarbonate to alkalize your urine. If you are randomized to the standard 
of care group, you will receive routine treatment and will be asked to provide urine samples as part of the study 
during your hospital stay. If you are randomized to the study group you will be given the medication 
intravenously and you will be asked to provide blood specimens to monitor your condition, and urine samples 
as part of the study during your hospital stay. We will be collecting some pertinent information from your 
medical record both during and from before your hospital stay. The blood and urine sample collections will 
happen during your hospital stay. 
Do I have to participate and what are the risks involved? 
Participation in this research study is completely voluntary and you are free to withdraw from the 
research at any time. If you do not wish to participate, please discuss alternatives with the study doctor or refer 
to the “Alternatives” section in the consent form. You may not directly benefit from participating in this 
research. 
Risks from participation in this study are minimal and may include some pain and a small risk of 
bleeding, bruising, or infection at the puncture site for the blood draws. There is also a small risk of fainting. 
These risks will be minimized by making every attempt to collect your blood samples from existing catheters in 
one of your veins or arteries to reduce the need for additional needle punctures if possible. We will make every 
attempt to coordinate our blood draw at the time you are to receive your blood draw for your standard of care 
treatment. However, there may be situations when we may have to get a separate blood draw. Sodium 
bicarbonate has been used in different treatment protocols for many years so its risks are generally well known. 
It is usually well tolerated but people may develop metabolic alkalosis (high base level in body), low calcium 
levels or hypervolemia (high fluid level in body). Alkalization of urine with sodium bicarbonate can also 
increase the elimination of certain drugs including hydroxychloroquine. You will be carefully monitored for 
these adverse effects during the study period. Though there is a lot of experience with sodium bicarbonate, there 
is always a risk of uncommon or previously unknown side effect(s) or event. 
 
Who can I talk to if I have questions or concerns? 
If you have any questions or concerns about this research or would want to withdrawal from the study, you can 
contact Dr. Ankit Sakhuja at 304-598-6092 from the Division of Cardiovascular Critical Care, Department of 
Cardiovascular and Thoracic Surgery at WVU Medicine. 
For more information, please see the Informed Consent Form. 


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Informed Consent for Research | More than Minimal Risk 
Principal Investigator (PI) | 
Ankit Sakhuja, MD 
Department | 
Division of Cardiovascular Critical Care, Department of 
Cardiovascular and Thoracic Surgery 
Sponsor or Funding Source | 
WVCTSI 
WVU IRB Protocol # | 
2005006707 
Study Title | 
Coronavirus Induced Acute Kidney Injury: Prevention using Urine 
Alkalinization 
Introduction 
You, 
, have been asked to participate in this research study which involves 
determining the feasibility and safety of a treatment protocol of acute kidney injury in patients with COVID-19 who 
are hospitalized, which has been explained to you by 
. This study is being conducted 
by Ankit Sakhuja, MD in the Department of HVI Critical Care Medicine at West Virginia University. 
Purpose 
The purpose of this study is to better understand how COVID-19 impacts patients’ kidneys. Since this virus is new, 
there is not a lot of information available for doctors and clinical staff on how the disease behaves, how to treat 
patients, and the outcomes of patients. COVID-19 is known to affect kidney function and cause AKI. Preventing 
AKI early on in COVID-19 patients may help reduce the overall burden and complications of AKI as the COVID- 
19 disease progresses. 
The main objective of this study is to determine the role of urine alkalization in prevention of the development and 
progression of AKI in critically ill patients with COVID-19. Urine alkalization is a process that helps to lower high 
levels of acid in the blood or urine that can be caused by certain medicines or conditions. This study hopes to better 
understand how COVID-19 impacts the patient’s kidneys. 
Medical information as well as biospecimens (blood and urine samples) from patients who test positive for COVID- 
19 can provide important information to doctors and clinical staff on better ways to treat patients. This study will 
randomly assign you to either the standard of care (control) or study (intervention) group. If you are randomized to 
the study group you will be given an intravenous medication called sodium bicarbonate to alkalize your urine. If 
you are randomized to the standard of care group, you will receive routine treatment and will be asked to provide 
urine samples as part of the study during your hospital stay. If you are randomized to the study group you will be 
given the medication intravenously and you will be asked to provide blood specimens to monitor your condition, 
and urine samples as part of the study during your hospital stay. We will be collecting some pertinent information 
from your medical record both during and from before your hospital stay. The blood and urine sample collections 
will happen during your hospital stay. We are planning to enroll approximately 40 patients at WVUMedicine. 
Description of Procedures 
This study involves assigning you to one of two groups and collecting blood and urine samples during your 
hospitalization. 
If you agree to be a part of this study, you will have the procedures described below: 


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• 
Review of medical history: You agree to allow the study staff to review your medical records to learn more 
about your general medical history including any illnesses you have, prior treatments, prior testing, 
procedures, etc. 
• 
Review of medications: You agree to allow the study staff to review your medical records to learn about 
medications that you are have taken in the past, are currently taking at the start, and throughout thestudy. 
• 
Physical exam and vital signs: You agree to allow the study staff to review your medical records to learn 
about information from your physical examinations prior to and during your hospital stay, including height, 
weight, temperature, blood pressure, and pulse. 
• 
If you are randomized to the control group, your care will be managed according to routine procedures. The 
only part of your participation that will be extra will be a collection of urine. We will collect urine from an 
existing catheter up to 3 times throughout your hospital stay. This urine would normally be disposed of, so 
there is nothing additional we need to do to you to collect this specimen. 
• 
If randomized to the study group the following will be done: urine alkalinization medication will be 
initiated and continued for 10 days or until you are discharged from the ICU or step-down unit, develop 
stage 3 AKI, or the safety end point of maintaining your fluid balance is reached. 
o There are tests necessary to monitor your condition. Many of these tests are already performed as part 
of your routine care. We will use as many of the test we can from your routine care. This study will 
simply ensure that these measurements are timed to maximize your safety. If for any reason you would 
not have the necessary tests as part of your routine care, we would need to draw blood and urine to 
perform them. 
 
Blood Collection: Some of these blood samples will be collected every 12 hours and some every 24 
hours. If they are not already done as part of your routine care, the most we would draw would be 
two (2) blood draws every day for up to ten (10) days. One blood draw would be about 2mL (about 
2/3 of a teaspoon) and the other one about 1.5mL (about 1/3 of a teaspoon). The total amount of 
blood that could be drawn for the entire study is about 60mL (about 12 teaspoons). The least you 
could have drawn is zero (0). Again, many of these are drawn for your routine care. 
• Blood will be collected to perform tests specifically related to your acid-base status, kidney 
functioning and electrolyte levels. If needed for the study, blood will be collected at multiple 
times from an existing catheter (tube) in one of your veins or arteries if possible to reduce the 
need for additional needles. If it is not possible to collect blood from an existing catheter (tube), 
then blood will be drawn by a routine needle puncture of a vein (usually in the arm). We will 
make every effort possible to do this at the time you get your routine care labs collected to limit 
the number of times you get a needle puncture. You will be monitored by study personnel after 
blood collection to see if you are experiencing any unwanted side effects. 
 
Urine Collection: Urine will be collected every 2-4 hours until the target pH is reached and 
then every 6-8 hours to ensure urine pH is in the appropriate range for urine alkalinization 
(≥7.2). Your urine is routinely discarded, so we will collect it before being discarded. 
• 
For both groups of patients, we will be storing some of your urine samples for future research. This urine 
would be routinely disposed of. We are also asking for your permission to store some of your health 
information with your samples so that your samples will be more useful for research. We plan to continue to 
review your medical record to update your health information. 
Risks and Discomforts 
Blood drawing may cause some pain and has a small risk of bleeding, bruising, or infection at the puncture site. 
There is also a small risk of fainting. These risks will be minimized by collecting your blood samples from existing 
catheters in one of your veins or arteries to reduce the need for additional needle punctures if possible. If not 


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possible, we make every attempt to coordinate our blood draw at the time you are to receive your blood draw for 
your standard of care treatment. 
Sodium bicarbonate has been used in different treatment protocols for many years so its risks are generally well 
known. It is usually well tolerated but people may develop metabolic alkalosis (high base level in body), low 
calcium levels or hypervolemia (high fluid level in body). Alkalization of urine with sodium bicarbonate can also 
increase the elimination of certain drugs including hydroxychloroquine. You will be carefully monitored for these 
adverse effects during the study period. Though there is a lot of experience with sodium bicarbonate, there is always 
a risk of uncommon or previously unknown side effect(s) or event. 
The risk from allowing your samples and health information to be stored is the potential loss of privacy; however, 
we will make every effort to protect your privacy by labeling your samples and information only with a code and 
keeping the key to the code unavailable to other researchers. 
In addition, there is always the risk of uncommon or previously unknown side effect(s) or event. 
Alternatives 
You do not have to participate in this study. 
Benefits 
You may not directly benefit from participating in this research. The knowledge gained from this study may help us 
understand, prevent, treat, or cure the illnesses and conditions studied. The knowledge gained from this study may 
eventually benefit others. 
Financial Considerations 
If you are in the study group, the study sponsor, WVCTSI, will pay for the costs of the sodium bicarbonate and the 
lab tests associated with managing your care while on the medication, that would not be part of current therapy for 
your disease or condition. If you are in the control group, your routine care will be billed to you or your insurance. 
Volunteering to participate in this study will be at no extra cost to you nor will you be compensated for 
participating. 
Your information may be provided to the appropriate parties for billing and/or payment purposes. Please be advised 
that any compensation received for participation in a research study, including a gift card, is considered taxable 
income and must be reported to the Internal Revenue Service (IRS). 
Your data, health information, research results, specimens, or any and all other information related to this research 
study used in this research study may contribute to a new discovery or treatment. In some instances, your data, your 
health information, your research results, your specimens, these discoveries or treatments, or any other information 
related to this research study, even if identifiers are removed, may be of commercial value and may be sold, 
patented, or licensed by the investigators and West Virginia University for use in other research or the development 
of new products. You will not retain any property rights nor will you share in any money or commercial profit that 
the investigators, West Virginia University, or their agents may realize. 
Confidentiality 
Any information about you that is obtained as a result of your participation in this research will be kept as 
confidential as legally possible. Your research records and test results, just like hospital records, may be 
subpoenaed by court order or may be inspected by the study sponsor or federal regulatory authorities, including the 
Food and Drug Administration (FDA), without your additional consent. 


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In addition, there are certain instances where the researcher is legally required to give information to the appropriate 
authorities. These would include mandatory reporting of infectious diseases, mandatory reporting of information 
about behavior that is imminently dangerous to you or to others, such as suicide, child abuse, etc. 
In any publications that result from this research, neither your name nor any information from which you might be 
identified will be published without your consent. 
Identifiers will be removed from the identifiable private information and the identifiable biospecimens and after that 
removal information or biospecimens by be used for future research studies or distributed to another investigator for 
future research studies without additional informed consent. 
This research is not planning to include whole genome sequencing. 
ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time. 
HIPAA Authorization 
We know that information about your health is private. We are dedicated to protecting the privacy of that 
information. Because of this promise, we must get your written authorization (permission) before we may use or 
disclose your protected health information or share it with others. 
You can decide to sign or not to sign this authorization section. However, if you choose not to sign this 
authorization, you will not be able to take part in the research study. Whatever choice you make about this research 
study will not have an effect on your access to medical care. 
Persons/Organizations Providing the Information 
Patient/West Virginia University Hospitals/WVU Medicine/WVUHS 
Persons/Organizations Receiving the Information 
• 
The research site(s) carrying out this study. This includes UHA or UHA Affiliates, WVU, WVU Hospitals, 
West Virginia University Health System (WVUHS). It also includes each site’s research and medicalstaff. 
• 
Health care providers who provide services to you as part of this researchstudy. 
• 
Laboratories and other people and groups that look into your health information as part of this study in 
agreement with the study protocol. 
• 
The United State Department of Health and Human Services (which includes the National Institutes of 
Health (NIH), Food and Drug Administration (FDA)) and other groups that have the right to use the 
information as required by law. 
• 
WVCTSI and the people that they use to oversee, manage, or conduct the research. 
• 
The members and staff of any institutional review board that oversees this research study. 
• 
The West Virginia University Office of Human Research Protection and the West Virginia University 
Office of Sponsored Programs. 
• 
WVU Heart and Vascular Institute (HVI) and our partner institutions involved in the study. 
The Following Information Will Be Used 


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Information from your existing medical records, and new information about you that is created or collected during 
this study, such as: history and physicals, clinic visit notes, nursing and staff notes, laboratory results, x-rays, EKG 
results, demographic data, pulmonary tests, imaging scans, and study forms. 
The Information is Being Disclosed for the Following Reasons 
• 
Review of your data for quality assurance purposes 
• 
Publication of study results (without identifying you) 
• 
Other research purposes such as reviewing the safety or effectiveness of the study drug, developing a better 
understanding of COVID-19, and improving the design of future studies. 
You may Cancel this Authorization at Any Time by Writing to the Principal Investigator 
Ankit Sakhuja, MD 
1 Medical Center Drive, Box 8003 
Morgantown, WV 26506 
If you cancel this authorization, any information that was collected already for this study cannot be withdrawn. 
Once information is disclosed, according to this authorization, the recipient may re-disclose it and then the 
information may no longer be protected by federal regulations. 
You have a right to see and make copies of your medical records. You will not be able to see or copy your records 
related to the study until we have completed all work related to the study. At that time, you may ask to see the study 
doctor’s files related to your participation in the study and have the study doctor correct any information about you 
that is wrong. 
This authorization will expire at the end of the study unless you cancel it before that time. 
Voluntary Compensation 
There is no money set aside to help treat you if you get hurt or sick in this study. The study doctor and WVU or its 
partners do not have special funds to pay for research related injuries if they occur. 
If you are injured as a result of this research, treatment will be available. This care will be billed to you or your 
insurance company. There is no commitment to provide any compensation for research-related injury. You should 
realize, however, that you have not released this institution from liability for negligence. Please contact the 
investigator, Dr. Ankit Sakhuja at 304-598-6092 if you are injured or for further information. 
Voluntary Participation 
Participation in this study is voluntary. You are free to withdraw your consent to participate in this study at any 
time. If you choose to withdraw your participation from the study, the data and biospecimens collected on you up 
until that time remains a part of the study database and may not be removed. No additional information will be 
added to the study database after your withdrawal. 
Refusal to participate or withdraw will not affect your future care or status at West Virginia University. 
In the event new information becomes available that may affect your willingness to participate in this study, this 
information will be given to you so that you can make an informed decision about whether or not to continue your 
participation. 
Incidental Findings 


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Generally, tests done for research purposes are not meant to provide clinical information. If it is determined that 
information generated from this research is clinically relevant to you individually, the Principal Investigator, Dr. 
Ankit Sakhuja, or his delegated staff will contact you. 
Contact Persons 
If you have any questions, concerns, or complaints about this research, you can contact Dr. Ankit Sakhuja at 304- 
598-6092. You can also contact Study Personnel at 304-598-6092. 
If you are hurt from being in this research, you should contact Dr. Ankit Sakhuja at 304-598-6092. If injury occurs 
outside of business hours and is related to your participation in this research, please contact Dr. Ankit Sakhuja at 
304-598-4478 
For information regarding your rights as a participant in research or to talk about the research, contact the WVU 
Office of Human Research Protection (OHRP) at (304) 293-7073 or by email at IRB@mail.wvu.edu. 
Future Contact 
Future research may be conducted for which you are eligible. If you are interested in being contacted for future 
research, please indicate so by completing this section. 
□ Yes, I want to be contacted if future research studies, for which I am qualified, become available. 
□ No, I do not want to be contacted if future research studies, for which I am qualified. 
Signatures and Authorization 
You have been given the opportunity to ask questions about the research (if applicable) and your authorization of 
HIPAA, and you have received answers concerning areas you did not understand. Upon signing this form, you will 
receive a copy. 
Participant Signature 
I willingly consent to participate in this research. 
 
 
Signature of Subject or Subject’s Legal Representative 
 
 
Printed Name 
Date 
Consenting Individual Signature 
The participant has had the opportunity to have questions addressed. The participant willingly agrees to be in the 
study. 
 
 
Signature of Person Obtaining Informed Consent 
 
 
Printed Name 
Date 
Impartial Witness Signature (if applicable) 
The participant or legal representative has had the opportunity to have questions addressed. As the impartial witness, 
I confirm that the participant willingly agrees to be in the study. 
 
 
Signature of Impartial Witness 
 
 
Printed Name 
Date