Trimethoprim-Sulfamethoxazole (TMP/SMX) Prophylaxis After Acute Kidney Injury to Prevent Post-discharge Infections
Phase: PHASE2
Conditions: Acute Kidney Injuries, Acute Kidney Disease, Acute Kidney Injury (AKI)
Sponsor: Hospital Civil de Guadalajara

 
                      
OPD HOSPITAL CIVIL DE GUADALAJARA  
ANTIGUO HOSPITAL CIVIL DE GUADALAJARA 
“FRAY ANTONIO ALCALDE” 
  
  
Protocol Title: 
Infectious Prophylaxis with Trimethoprim–Sulfamethoxazole 
Following Severe Acute Kidney Injury: A Clinical Trial at the Old 
Civil Hospital of Guadalajara, from October 2025 to October 2026 
 
 
 
 
 
Presented by: 
Ronaldo Escoto Del Toro 
  
 
Thesis Director: 
Jonathan Samuel Chávez Íñiguez 
 
 
 
 
 
 
 
 
Guadalajara, Jalisco — October 15, 2025
 
CIVIL HOSPITAL OF GUADALAJARA
FRAY ANTONIO ALCALDE
Guadalajara, November 1, 2025

 
Table of Contents 
 
Contents 
 
Abbreviations ................................................................................................................ 3 
Introduction ................................................................................................................... 4 
Background ................................................................................................................... 4 
Problem Definition ......................................................................................................... 5 
Justification .................................................................................................................... 5 
Theoretical and Conceptual Framework ........................................................................ 6 
Study Objectives ............................................................................................................. 6 
Working Hypothesis (if applicable) ................................................................................. 6 
Materials and Methods ................................................................................................... 7 
Population Universe ....................................................................................................... 7 
Observation Unit ............................................................................................................ 7 
Sample Size ................................................................................................................... 7 
Sampling Method ........................................................................................................... 8 
Inclusion Criteria ............................................................................................................ 8 
Exclusion Criteria ........................................................................................................... 8 
Elimination Criteria ......................................................................................................... 8 
Operationalization of Variables ...................................................................................... 8 
Data Collection and Observation Techniques ................................................................ 9 
Statistical Analysis .......................................................................................................... 9 
Presentation of Information ........................................................................................... 10 
Required Resources ..................................................................................................... 10 
Dissemination ............................................................................................................... 10 
Bibliographic References .............................................................................................. 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
​
 
​
 
Abbreviation 
 

 
 
(AKI) – Acute Kidney Injury 
(ICU) – Intensive Care Unit 
(KDIGO) – Kidney Disease: Improving Global Outcomes (Organization) 
(SCr) – Serum Creatinine 
(UO) – Urine Output 
(CI) – Confidence Interval 
(HR) – Hazard Ratio 
(eGFR) – Estimated Glomerular Filtration Rate 
(CKD) – Chronic Kidney Disease 
(IQR) – Interquartile Range 
(AE) – Adverse Events 
(MAKE) – Major Adverse Kidney Events 
(RRT) – Renal Replacement Therapy 
(TMP-SMX) – Trimethoprim–Sulfamethoxazole 
​
 
​
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
​
 
​
Introduction 
Acute kidney injury (AKI) is a complex disorder characterized by a rapid decline in renal 
function, leading to the accumulation of metabolic waste products and fluid imbalance. It 
is a frequent and severe complication among critically ill patients, affecting 
approximately 30–50% of those admitted to intensive care units (ICUs). This syndrome 
 

 
is associated with increased morbidity, mortality, and healthcare costs. 
The prognosis of AKI depends on its severity and underlying cause. The worst 
outcomes are observed in patients who require renal replacement therapy (RRT), in 
whom mortality approaches 60%. AKI is often secondary to non-renal organ dysfunction 
such as sepsis, respiratory failure, or heart failure. These conditions may reduce renal 
perfusion and promote inflammation and oxidative stress, resulting in kidney injury. 
Although the KDIGO consensus criteria provide a standardized definition of AKI based 
on changes in serum creatinine (SCr) and urine output (UO), these markers tend to 
appear late and lack sensitivity for early detection. Moreover, survivors of AKI have 
been shown to face a markedly increased risk of infections, particularly within the first 
three months after hospital discharge. This heightened susceptibility is mainly due to a 
state of multifactorial immunosuppression and cellular anergy. 
​
 
​
 
Background 
​
Following an episode of AKI, infections are a frequent complication. 
​
In a retrospective Spanish cohort, infection surveillance began three months after 
the AKI episode. Over a median follow-up of nine months (IQR 2–56), 153 patients 
(42%) developed at least one infection. The most common were urinary tract 
infections [67 (44%)], respiratory tract infections [46 (30%)], soft tissue infections 
[14 (9%)], and abdominal infections [14 (9%)]. No specific baseline variable was 
associated with infection type. 
​
Factors linked to infection during follow-up were analyzed using Cox regression. In 
univariate analysis, the following were associated with infection risk: older age {HR 
1.18 [95% CI, 1.05–1.33], P = 0.005}, cognitive impairment [HR 1.51 (95% CI, 
1.00–2.28), P = 0.050], lower eGFR three months post-AKI [HR 0.91 (95% CI, 
0.86–0.97), P = 0.002], decline in eGFR from baseline to three months [HR 1.07 
(95% CI, 1.01–1.14), P = 0.028], and transition from AKI to chronic kidney disease 
(CKD) [HR 1.55 (95% CI, 1.13–2.14), P = 0.007]. 
​
Baseline eGFR differed significantly between patients who developed infection and 
those who did not (P = 0.038), although the nadir and post-AKI eGFR values were 
similar between groups (P = 0.289 and P = 0.215, respectively).
 

 
Problem Definition 
 
Study Rationale: 
●​ Infections represent a serious yet understudied complication among patients who 
have experienced acute kidney injury (AKI). While kidney disease is known to 
increase susceptibility to infections—and infections are a major cause of mortality 
in this population—the precise relationship between AKI and infection risk, as 
well as the immunologic mechanisms underlying this vulnerability, remain poorly 
understood. 
●​ Existing data indicate that postoperative AKI is associated with higher rates of 
infection-related hospitalizations, and that the transition from AKI to chronic 
kidney disease (CKD) further amplifies infectious risk. However, to date, no 
studies have evaluated the efficacy of antibiotic prophylaxis in preventing 
infections among patients recovering from severe AKI after hospital discharge. 
●​ This research gap underscores the need for a clinical trial aimed at determining 
whether prophylactic administration of trimethoprim–sulfamethoxazole can 
reduce infection incidence in this high-risk group. 
 
Research Question: 
Does administration of trimethoprim–sulfamethoxazole 800/160 mg every 48 hours 
for 90 days reduce the risk of infections in patients who have experienced 
severe acute kidney injury after hospital discharge? 
​
 
Justification 
​
The justification for this study lies in the absence of previous clinical trials evaluating 
the effectiveness of antibiotic prophylaxis in reducing infection risk following acute 
kidney injury (AKI) among discharged patients. Identifying infections as one of the 
most underestimated complications in AKI highlights the urgent need to address 
this research gap. Implementing a clinical trial to evaluate the administration of 
trimethoprim–sulfamethoxazole could provide crucial data regarding its efficacy and 
contribute to improving medical care and health outcomes in this vulnerable 
population. 
​
The significance of this study is reflected in its potential to influence clinical practice 
and improve the management of AKI patients. Reducing infections may not only 
decrease morbidity but also enhance quality of life and lessen the healthcare 
system’s burden. As the first study of its kind, its findings could establish a 
precedent for future research and guide the development of antibiotic prophylaxis 
protocols in similar clinical contexts. 
​
The feasibility of the study is supported by its design—a randomized, double-blind, 
placebo-controlled clinical trial—which aligns with current recommendations for 
addressing AKI. The selection of Hospital Civil de Guadalajara “Fray Antonio 
Alcalde” as the research center ensures access to a relevant AKI patient 
population. Furthermore, clearly defined inclusion criteria and randomization 
methods suggest adequate planning to ensure successful recruitment and 
adherence to the protocol. 
​
Potential vulnerabilities of the study include the possibility of bias during 
randomization or outcome assessment, as well as limited generalizability of findings 
to other populations due to cultural, socioeconomic, or healthcare delivery 
differences. Additionally, since this study targets a critically ill population, adverse 
 

 
events related to antibiotic use will represent an important consideration. 
Addressing these aspects is essential for the validity and interpretation of the 
study’s findings. 
 
 
Theoretical and Conceptual Framework 
​
Infections are among the least studied consequences of AKI. Although kidney 
diseases are well-recognized risk factors for infections—and infections remain one 
of the leading causes of death among patients with renal disease—the underlying 
mechanisms of this secondary immunodeficiency remain poorly defined [Steiger S]. 
​
Regarding the bidirectional relationship between AKI and infections, the recently 
published NARA-AKI prospective study demonstrated that postoperative AKI in 
non-cardiac surgery was associated with increased hospitalizations due to 
infections [Tagawa M, Kellum JA]. Beyond AKI, patients with chronic kidney disease 
(CKD) are more vulnerable to infections and exhibit worse outcomes than cohorts 
without CKD [Xu H, Su G]. Interestingly, not only the progression from AKI to CKD 
but also the decline in eGFR—independent of baseline or post-AKI eGFR—was 
independently associated with infection risk. 
​
Several mechanisms may explain this increased susceptibility to infection. The 
immune dysfunction of CKD—characterized by impaired innate and adaptive 
immunity, decreased clearance of proinflammatory cytokines, and even epigenetic 
modifications in hematopoietic stem cells—adds to the alterations seen in AKI, such 
as disrupted kidney-immune system crosstalk, changes in immune cell composition 
and function, and an exaggerated inflammatory response [LaFavers K, 
Syed-Ahmed M]. Nevertheless, the precise pathophysiology of the elevated 
infection risk in patients transitioning from AKI to CKD remains incompletely 
understood. 
​
Finally, a retrospective cohort study (Griffin BR) showed that recovery from AKI was 
associated with a 4.5-fold increase in the likelihood of infection (OR 4.53 [95% CI, 
2.43–8.45]; p < 0.0001) within 30 days after hospital discharge. Moreover, the 
association between AKI and subsequent infection remained significant at 31–60 
days and 91–365 days post-discharge, but not during the 61–90-day interval. 
​
 
Study Objectives 
​
Primary Objective: 
​
To reduce the risk of infections within 90 days following hospital discharge after a 
severe episode of acute kidney injury (AKI). 
​
Secondary Objectives: 
​
To evaluate the risk of rehospitalization, infection-related rehospitalization, septic 
shock, major adverse kidney events (MAKE) at 90 days, incidence of hyperkalemia, 
and new episodes of acute kidney injury. Adverse events (AEs) will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and classified as mild, 
moderate, or severe. AEs of special interest include skin rash, erythema, nausea, 
vomiting, headache, and tachycardia. 
 
 
Working Hypothesis 
 
Hypothesis: Administration of trimethoprim–sulfamethoxazole 800/160 mg every 48 
hours for 90 days reduces the risk of infections. 
 

 
 
Null Hypothesis: Administration of trimethoprim–sulfamethoxazole 800/160 mg every 48 
hours for 90 days does not reduce the risk of infections. 
​
 
 
 
 
 
Materials and Methods 
• This study will be a phase 2, randomized, prospective, double-blind, 
investigator-initiated, parallel-group, placebo-controlled clinical trial conducted at the 
Hospital Civil de Guadalajara “Fray Antonio Alcalde”, Guadalajara, Mexico. All patients 
with AKI receiving nephrology consultation will be considered for inclusion. 
• The diagnosis of AKI will follow the Kidney Disease: Improving Global Outcomes 
(KDIGO) serum creatinine criteria. In accordance with the recommendations of the 31st 
Acute Disease Quality Initiative Group regarding the design of clinical trials for AKI 
treatments, the subphenotype of patients at the highest risk of post-AKI infections will 
be selected. This study will be considered a phase 2 randomized, double-blind, 
placebo-controlled trial meeting efficacy (AKI trajectory and eGFR evaluation), feasibility 
(patient recruitment and protocol adherence), and safety (adverse events and drug 
reactions) objectives. 
• Group randomization will be performed using the clinical trial randomization tool 
available at http://www.winepi.net/f108.php, employing traditional block randomization. 
Sequences for each arm and stratum will be generated using maximal asymptotic 
randomization. 
• Patients will be recruited on an outpatient basis to document any infectious event of 
any kind occurring within the first 90 days, as well as cases of rehospitalization due to 
infection within the same period at the Hospital Civil de Guadalajara “Fray Antonio 
Alcalde”. 
 
Study Population 
Patients diagnosed with severe acute kidney injury (AKI) who have been discharged 
from the hospital and receive nephrology follow-up at the Hospital Civil de Guadalajara 
“Fray Antonio Alcalde”, Guadalajara, Mexico. This group will include patients with 
diverse demographic and clinical characteristics who meet the inclusion criteria 
established in the study protocol. 
 
​
Observation Unit 
Patients diagnosed with severe AKI will be monitored for a period of 90 days after 
hospital discharge. Each participant will be evaluated based on infection incidence, 
rehospitalization, adverse events, and other health outcomes related to 
trimethoprim–sulfamethoxazole administration. Observation will focus on collecting 
clinical data and health outcomes specific to each participant. 
 
​
Sample Size 
To determine, with a 95% confidence level and 90% statistical power, whether the 
proportion of 59% in sample A differs from 29.5% in sample B, a total of 60 individuals 
per group will be required. 
This study aims to detect a clinically significant difference of 0.8 (Zα/2 = 1.96, Zβ = 0.84) 
with a standard deviation of 1.5. Sample size calculations are based on the assumption 
 

 
that approximately 30% of patients with AKI will experience a subsequent infection. 
 
 
 
 
 
 
 
 
 
 
Sampling Method 
​
Potential participants for this study will be identified during routine hospital rounds 
for patients with acute kidney injury (AKI) and through concurrent review of medical 
records to confirm eligibility. If a patient is deemed eligible, the principal investigator 
will contact them to explain the study and provide a participant information and 
consent form. 
​
After discussion with the patient and family members, the nephrology staff will 
obtain written informed consent prior to any study-related evaluations. 
​
The intervention drug will be trimethoprim–sulfamethoxazole 800/160 mg, 
administered under double-blind conditions. Blinding will be achieved by ensuring 
that participants do not witness preparation of the study medication, and by 
assigning unblinded study personnel—who will not participate in outcome 
assessments—to handle preparation and administration. 
​
The placebo will consist of magnesium tablets, administered at the same 
frequency—one tablet every 48 hours for three months. 
​
 
 
Control Group Definition 
The control group will include patients who, during hospitalization at the Old Civil 
Hospital of Guadalajara “Fray Antonio Alcalde”, were identified by the Nephrology 
Service as having severe acute kidney injury that had resolved or was in the process of 
recovery. These patients will have been discharged with standard post-AKI 
management and care, without the addition of antibiotic prophylaxis. 
 
Inclusion Criteria 
Patients with severe AKI and known baseline serum creatinine (SCr) levels—defined as 
the most recent SCr value within the six months preceding hospitalization—will be 
included. Participants must also have available serum creatinine data for the months 
following discharge to assess major adverse kidney events (MAKE) at 90 days 
post-AKI. 
 
 
Exclusion Criteria 
Patients will be excluded if they: Experienced AKI within the previous three months, Are 
younger than 18 years, Have CKD stage 5, chronic dialysis, or kidney transplant, Had a 
hospital stay shorter than 48 hours, Have incomplete data preventing full análisis 
 
​
 
Elimination Criteria 
 

 
●​ Patients who partially or completely discontinue the prophylactic antibiotic 
before completing three months of treatment 
●​ Patients rehospitalized for non-infectious causes within the first three 
months 
●​ Patients who take a different dose of prophylactic antibiotic than 
prescribed 
​
 
 
Operationalization of Variables 
 
Independent Variable: 
●​ Treatment: Administration of the study drug versus placebo (categorical variable 
with two levels: active treatment or placebo). 
Dependent Variables (Primary Outcomes): 
●​ Development of gastrointestinal infections — categorical nominal binary variable 
(yes/no) 
 
●​ Development of upper respiratory infections — categorical nominal binary 
variable (yes/no) 
●​ Development of lower respiratory infections — categorical nominal binary 
variable (yes/no) 
●​ Development of urinary tract infections — categorical nominal binary variable 
(yes/no) 
●​ Development of soft tissue infections — categorical nominal binary variable 
(yes/no) 
●​ Rehospitalization due to infection — categorical nominal binary variable (yes/no) 
●​ Development of septic shock — categorical nominal binary variable (yes/no) 
●​ Requirement for long-term renal replacement therapy — categorical nominal 
binary variable (yes/no) 
●​ Death from any cause — categorical nominal binary variable (yes/no) 
●​ Progression to chronic kidney disease or ≥50% decline in eGFR — categorical 
nominal binary variable (yes/no) 
●​ Worsening renal function with ≥25% decline in eGFR due to infection — 
categorical nominal binary variable (yes/no) 
●​ Presence of hyperkalemia — categorical nominal binary variable (yes/no) 
●​ Adverse drug reactions — categorical nominal variable 
 
 
Data Collection and Observation Techniques 
 

 
​
Data will be collected through automated extraction from the institutional electronic 
medical record system. Additional potential contributors to AKI—such as 
nephrotoxic medications (aminoglycosides, nonsteroidal anti-inflammatory drugs, 
and vancomycin)—will also be considered. 
​
The presence of anaphylactic shock will be documented, and relevant biochemical 
parameters, such as serum iron levels and transferrin saturation, will be recorded 
for analysis. 
​
Indications for renal replacement therapy (RRT) will include: 
●​ Fluid overload refractory to diuretics 
●​ Severe hyperkalemia 
●​ Severe metabolic acidosis 
●​ Uremic manifestations such as encephalopathy, pericarditis, or seizures 
​
The study will be submitted to the Institutional Review Board (IRB) of the Hospital 
Civil de Guadalajara “Fray Antonio Alcalde” and registered at ClinicalTrials.gov with 
the corresponding registration number. 
This research will adhere to the ethical principles outlined in the Declaration of Helsinki 
and will be designed in accordance with CONSORT (Consolidated Standards of 
Reporting Trials) guidelines. 
 
Statistical Analysis 
​
An intention-to-treat approach will be adopted, including all randomized participants 
who receive the intervention, for both primary and secondary outcomes. 
​
Categorical variables will be expressed as counts and percentages (%) and 
compared using either the chi-square test or Fisher’s exact test, as appropriate. 
Continuous variables will be reported as median values (IQR), since normal 
distribution is not expected according to the Shapiro–Wilk test; between-group 
comparisons will be performed using the Mann–Whitney U test. 
​
A repeated-measures analysis of variance (ANOVA) will be used to compare 
variables over time between groups. A Kaplan–Meier survival curve will be plotted 
for both groups and compared using the log-rank test. Missing data will be imputed 
using the mean linear interpolation method. 
​
All statistical tests will be two-tailed, and a p-value < 0.05 will be considered 
statistically significant. 
​
The analyses and figures will be performed using MedCalc software (Version 
22.0.21, Ostend, Belgium) and GraphPad Prism (Version 10.2.3, Boston, 
Massachusetts, USA). 
 
 
 
Presentation of Information 
 
●​ Table of demographic characteristics comparing the intervention and control 
groups 
●​ Quantitative comparison table of reported infections 
●​ Kaplan–Meier comparative survival curve between intervention and control 
groups 
 
 
Required Resources 
●​ The database will be compiled by the supervising resident physician and the 
 

 
assigned medical intern. 
●​ Material resources required include: 
o​ Computer equipment for data collection 
o​ Supply of trimethoprim–sulfamethoxazole 800/160 mg tablets, 
administered every 48 hours for three months per patient 
o​ The trimethoprim–sulfamethoxazole tablets will be funded by the research 
team itself. 
 
 
Dissemination 
 
The study findings will be disseminated through scientific conferences, academic 
presentations, and peer-reviewed 
​
 
 
 
 
 
 
 
 
 
 
 
​
 
 
​
 
​
 
 

 
​
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