Coronavirus Induced Acute Kidney Injury: Prevention Using Urine Alkalinization
Phase: PHASE4
Conditions: COVID, Coronavirus, Coronavirus Infection, AKI, Acute Kidney Injury
Sponsor: West Virginia University

Approved:18-Feb-2021Expires:30-Jun-2021Number:2005006707 
 
 
 
 
 
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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