Renal Failure

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/irnf20

Probiotics in septic acute kidney injury, a double

blind, randomized control trial

Jonathan S. Chávez-Íñiguez, Miguel Ibarra‑Estrada, Alejandro Martínez

Gallardo-González, Ari Cisneros-Hernández, Rolando Claure-Del Granado,
Gael Chávez-Alonso, Eduardo M. Hernández-Barajas, Alexia C. Romero-
Muñoz, Fidel Ramos-Avellaneda, Manuel L. Prieto-Magallanes, Marcela
Plascencia-Cruz, Jarumi A. Tanaka-Gutiérrez, Cristina Pérez-Hernández,
Guillermo Navarro-Blackaller, Ramón Medina-González, Luz Alcantar-Vallin,
Karina Renoirte-López & Guillermo García-García

To cite this article: Jonathan S. Chávez-Íñiguez, Miguel Ibarra‑Estrada, Alejandro Martínez

Gallardo-González, Ari Cisneros-Hernández, Rolando Claure-Del Granado, Gael Chávez-
Alonso, Eduardo M. Hernández-Barajas, Alexia C. Romero-Muñoz, Fidel Ramos-Avellaneda,
Manuel L. Prieto-Magallanes, Marcela Plascencia-Cruz, Jarumi A. Tanaka-Gutiérrez, Cristina
Pérez-Hernández, Guillermo Navarro-Blackaller, Ramón Medina-González, Luz Alcantar-
Vallin, Karina Renoirte-López & Guillermo García-García (2023) Probiotics in septic acute
kidney injury, a double blind, randomized control trial, Renal Failure, 45:2, 2260003, DOI:
10.1080/0886022X.2023.2260003

To link to this article: https://doi.org/10.1080/0886022X.2023.2260003

© 2023 The Author(s). Published by Informa Published online: 19 Sep 2023.

UK Limited, trading as Taylor & Francis
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Renal Failure
2023, VOL. 45, NO. 2, 2260003
https://doi.org/10.1080/0886022X.2023.2260003

CLINICAL STUDY

Probiotics in septic acute kidney injury, a double blind, randomized

control trial
Jonathan S. Chávez-Íñigueza,b , Miguel Ibarra‑Estradac, Alejandro Martínez Gallardo-Gonzáleza,b,
Ari Cisneros-Hernándezd, Rolando Claure-Del Granadoe, Gael Chávez-Alonsob, Eduardo M.
Hernández-Barajasb, Alexia C. Romero-Muñoza,b, Fidel Ramos-Avellanedaa,b, Manuel L.
Prieto-Magallanesa,b, Marcela Plascencia-Cruza,b, Jarumi A. Tanaka-Gutiérrezb, Cristina
Pérez-Hernándezb, Guillermo Navarro-Blackallera, Ramón Medina-Gonzáleza, Luz Alcantar-Vallina,b,
Karina Renoirte-Lópeza,b and Guillermo García-Garcíab
a
Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico; bHealth Sciences Center, University
of Guadalajara, Guadalajara, Jalisco, Mexico; cIntensive Care Unit, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco,
Mexico; dDivision of Nutrition, NIN Institute, Guadalajara, Jalisco, México; eDivision of Nephrology, Hospital Obrero #2 – C.N.S,
Universidad Mayor de San Simon School of Medicine, Cochabamba, Bolivia

ABSTRACT ARTICLE HISTORY

Introduction: During acute kidney injury (AKI) due to sepsis, the intestinal microbiota changes to Received 20 July 2023
dysbiosis, which affects the kidney function recovery (KFR) and amplifies the injury. Therefore, the Revised 12 September
administration of probiotics could improve dysbiosis and thereby increase the probability of KFR. 2023
Methods: In this double-blind clinical trial, patients with AKI associated with sepsis were Accepted 12 September
2023
randomized (1:1) to receive probiotics or placebo for 7 consecutive days, with the objectives of
evaluate the effect on KFR, mortality, kidney replacement therapy (KRT), urea, urine volume, serum KEYWORDS
electrolytes and adverse events at day 7. AKI; sepsis; probiotics;
Results: From February 2019 to March 2022, a total of 92 patients were randomized, 48 to the intestinal dysbiosis
Probiotic and 44 to Placebo group. When comparing with placebo, those in the Probiotics did not
observe a higher KFR (HR 0.93, 0.52–1.68, p = 0.81), nor was there a benefit in mortality at 6 months
(95% CI 0.32–1.04, p = 0.06). With probiotics, urea values decreased significantly, an event not
observed with placebo (from 154 to 80 mg/dl, p = 0.04 and from 130 to 109 mg/dl, p = 0.09,
respectively). Urinary volume, need for KRT, electrolyte abnormalities, and adverse events were
similar between groups. (ClinicalTrial.gov NCT03877081) (registered 03/15/2019).
Conclusion: In AKI related to sepsis, probiotics for 7 consecutive days did not increase the
probability of KFR, nor did other variables related to clinical improvement, although they were
safe.

Introduction located on different sites of the nephron [5], promoting the

physiological functioning of the kidney and maintaining the
The intestinal microbiota comprises 100 trillion microorgan-
glomerular filtration rate (GFR) and tubular capacity to reab-
isms, such as bacteria, viruses, fungi, and protozoa, that inter-
sorb and secrete solutes, which is a process called symbi-
act with the human host during health and disease processes
[1,2] and have been fundamental in the evolution of humans osis [6].
[3,4]. The great majority of intestinal bacteria (∼90%) are cat- During disease and inflammation, the intestinal microbi-
egorized into three groups: Bacteroidetes, Firmicutes, and ome undergoes changes in its composition, causing the
Actinobacteria. During physiological states, they contribute proliferation of pathogenic bacteria, which in turn pro-
to the generation of short-chain fatty acids (SCFAs), which motes more local and systemic inflammation, elevated con-
considerably interact with the immune system and affect all centrations of uremic toxins, increased intestinal
organ functions. In the kidney, for example, they interact permeability, endotoxemia, and immunodeficiency [7,8],
with four SCFA receptors (Gpr41, Gpr43, Gpr109a, and Olfr78) affecting homeostasis through different pathways. This

CONTACT Jonathan S. Chávez-Íñiguez [email protected] Nephrology Service, Hospital Civil de Guadalajara Fray Antonio Alcalde, Hospital
278, Colonia Centro. C.P., Guadalajara, Jalisco 44150, Mexico
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the
Accepted Manuscript in a repository by the author(s) or with their consent.
2 J. S. CHÁVEZ-ÍÑIGUEZ ET AL.

phenomenon is called intestinal dysbiosis [6] and has been on 03/15/2019. No funding was received to conduct
associated with adverse clinical outcomes in experimental this study.
models and humans in many different clinical scenarios,
such as systemic inflammatory response syndrome [9], sep-
sis [10], chronic kidney disease (CKD) and acute kidney Definitions
injury (AKI) [11–14].
AKI was defined as an increase in serum creatinine (sCr) lev-
AKI occurs in one out of every four hospitalized
els according to Kidney Disease Improving Global Outcomes
patients, and 22.8% of these patients die during hospital-
(KDIGO) [26], and CKD was defined according to the KDIGO
ization [15,16]. The main cause of hospital-acquired AKI
guidelines [27]. The estimated glomerular filtration rate
(HA-AKI) is sepsis, which accounts for 70% of cases in our
(eGFR) in ml/min/1.73 m2 was calculated according to the
community. Various efforts to identify specific treatments
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
to attenuate sepsis-induced AKI, such as antifibrotics,
equation [28]. Baseline eGFR was considered according to
anti-inflammatory agents and immunomodulators, have
the more recent sCr level measured within the prior 3 months.
been unsuccessful [17,18]; therefore, the management of
For patients without baseline sCr values, we estimated it by
sepsis-induced AKI is currently limited to treating the main
back-calculating the Modification of Diet in Renal Disease
etiology [19] and, in severe cases, correcting its complica-
(MDRD) equation, assuming eGFR 100 mL/min/1.73 m; this
tions through kidney replacement therapies (KRTs) [20].
surrogate was preferred because it has been shown to be
There is an urgent need to explore alternatives for the
more accurate than assuming 75 mL/min/1.73 m2 [29]. Sepsis
treatment of AKI [21].
was defined according to the Sepsis-3 criteria [30]. Kidney
Since AKI is a syndrome that generates intense systemic
function recovery (KFR) was defined as the return of sCr lev-
inflammation [22], attenuation of this phenomenon has
els to <0.30 mg/dL from the baseline value after up to 7 days
been shown to improve renal function and parenchymal
of follow-up. Seven days was chosen to define renal recovery
damage [23,24]. AKI and intestinal dysbiosis coexist, ampli-
since after day 7, if patients do not recover from AKI, they
fying local and systemic inflammation and facilitating the
are considered to have developed acute kidney disease
proliferation of harmful intestinal bacteria, which generates
(AKD), and they have an increased risk of adverse outcomes
a vicious cycle that worsens clinical status and causes kid-
[31,32].
ney injury and subsequent systemic failure [14,25]. It seems
All comorbidities and clinical data were prospectively col-
reasonable that modulating the microbiota and improving
lected during the first evaluation.
intestinal dysbiosis during AKI by administrating probiotics
Adverse events were prespecified according to those most
could improve outcomes in patients with these syndromes.
frequently reported with the use of probiotics, such as
We conducted the first clinical trial of probiotic treatment
abdominal distension, nausea, rash, vomiting and diarrhea
for patients with sepsis-induced AKI (ClinicalTrial.gov
[33], and they were prospectively recorded on a daily basis
NCT03877081) (registered 03/15/2019) with the hypothesis
by the nephrology staff. Additional data were collected from
that by modulating intestinal dysbiosis with probiotics, AKI
the medical records and hospital electronic database.
recovery will improve.
Appropriate adherence to treatment was defined as >80% of
the administered capsules being consumed.

Methods
Study outcomes
Study participants
The primary outcome was KFR on day 7 (sCr return to
This was a single-center double-blind randomized clinical
<0.30 mg/dL from the baseline value). Secondary outcomes
trial that screened all consecutive patients admitted for AKI
included variables related to KFR during the treatment and
who met the diagnostic criteria for sepsis and had been eval-
the follow-up period, namely, the change in urinary volume,
uated by the Nephrology Department at the Hospital Civil de
percentage of decrease in sCr levels, in-hospital mortality,
Guadalajara Fray Antonio Alcalde, a large referral center that
mortality during follow-up, KRT requirement, electrolyte lev-
cares for patients without health care insurance and with low
els and acid–base abnormalities. The prespecified adverse
socioeconomic status in Jalisco, México.
events mentioned above were prospectively reported.
Patients were enrolled from February 2019 to March 2022.
Due to the COVID-19 pandemic, we enrolled patients at a
slower rate and over a relatively long period (2019 through
Randomization and treatment assignments
2021). The trial was conducted in accordance with the prin-
ciples of the Declaration of Helsinki and the International Randomization was carried out by a computer-generated
Conference on Harmonization Guidelines for Good Clinical stratified sequence with a 1:1 allocation ratio in blocks of 5,
Practice. All patients gave their written informed consent with the groups stratified by sex. The researchers, who used a
before any study-related procedure. The study, which was concealed opaque envelope system, performed group assign-
approved by the local ethics committee (HCG/CEI-1342/18), ment after informed consent was obtained. A double-blind,
was prospectively registered in clinicaltrials.gov (NCT03877081) double-dummy design was used. The nephrology staff
 Renal Failure 3

administered the treatment in white bottles that were only nonnormally distributed and were compared using Student’s
marked with the patient’s assignment number. t test or the Mann–Whitney U test, respectively. For variables
Given the lack of previous clinical trials on this topic, a measured at multiple time points, repeated measures analy-
formal sample size calculation was not performed, and we sis of variance tests were used for comparisons between
chose a convenient sample size of 92 patients. All patients groups. Time to renal recovery and time to death were both
received the personalized management suggested by the plotted on Kaplan–Meier curves, and the groups were com-
KDIGO AKI bundle of care guidelines [26]. The study design pared with the log-rank test. A multiple regression analysis
is described in Supplemental Figure 1. Inclusion criteria were was performed with the enter method, and all the baseline
age >18 years, the presence of sepsis-induced AKI, willingness variables with a p value ≤0.20 were entered into the model
to participate and signed informed consent. Patients with in bivariate analysis. All tests were two-tailed, and results
CKD KDIGO stages 4–5 or on chronic dialysis, kidney trans- with a p value less than 0.05 were considered significant.
plant, pregnancy, or who had not signed the informed con- Statistical analysis was performed, and graphics were gener-
sent form were excluded. ated with MedCalc Statistical Software (Ostend, Belgium. Ver
Patients who met the inclusion criteria and signed 19.1.3) and GraphPad Prism (California, USA. Ver 9.2.0),
informed consent were randomized to the intervention group respectively.
(probiotics) or the control group (placebo), and 2 capsules
per os (or through an enteral tube) were administered every
24 h. Blood and urine tests were performed to measure the Results
variables of interest every 24 h and were processed in a cer-
From February 2019 to March 2022, 621 patients with AKI
tified central laboratory.
underwent nephrology consultation, and 123 did not have
The results are reported following the CONSORT guide-
sepsis or they lacked variables of interest for the analysis;
lines for clinical trials.
thus, 498 were assessed for eligibility, among whom 372 did
not meet inclusion criteria, and 34 did not sign the consent
Interventions form; therefore, 92 patients were randomized, with 48 in the
intervention group (probiotics) and 44 in the placebo group
Patients in the intervention group received 2 capsules of
(Figure 1).
Simbin-RNL® or 2 capsules of placebo (maltodextrin) every
The baseline demographic characteristics of the random-
24 h for 7 consecutive days. The gastro-resistant Simbin-RNL®
ized study participants are described in Table 1. The mean
capsule contained 540 mg of a mixture of Streptococcus ther-
age was 56.9 ± 16.3 years, 51% [35] were female, almost half
mophilus, Lactobacillus acidophilus, Bifidobacterium longum
of them had diabetes (46%), and a quarter had CKD (27%).
(90 billion colony forming units (CFU) in the 2-capsule serv-
We did not observe any severe electrolyte alterations, and all
ing (4.5 x10e10 CFU per capsule), agave inulin (the contribu-
had mild metabolic acidosis (pH and HCO3, 7.33 ± 0.06 and
tion of prebiotic fiber per serving is 600 mg per 2 capsules),
19.1 ± 3.9, respectively). Most of the patients (92%) had severe
magnesium stearate and silicon dioxide. The Simbin-RNL®
AKI (KDIGO stages 2 and 3, 15% and 77%, respectively) with
formula comprises a mixture of a food supplement of probi-
a mean Sequential Organ Failure Assessment (SOFA) score of
otic strains and agave inulin (a prebiotic) that acts as soluble
6 [4–8], and 9.3% had septic shock.
fiber, which arrives intact in the intestine to be used as food
Regarding adherence, 81% in the probiotic group and
for the anaerobic intestinal microbiota, promoting the growth
77% in the control group consumed at least 80% of the
of saccharolytic bacteria and increasing the concentration of
doses (p = 0.63).
SCFAs; it also promotes alterations in intestinal pH, inhibition
of pathogens via the generation of antibacterial compounds,
competitive elimination of pathogens in receiver binding
Primary outcome
sites and competitive for available nutrients [7]. This formula
was chosen for this trial since it has shown kidney function The KFR by day 7 is presented in Table 2 and Figure 2. A
benefits in experimental models of AKI, improving kidney total of 40 (43%) patients had KFR, including 25 (50%) in
function measured by sCr and urea levels and attenuating the probiotic group and 21 (48%) in the control group, and
histological injury [10,34]. there was no significant difference (p = 0.82) between
groups. The relative risk for recovery on day 7 in the inter-
vention group was 0.93 (95% CI 0.52–1.68, p = 0.81). Thus,
Statistical analysis
no benefit was observed in patients who received probiot-
Categorical variables are presented as numbers and percent- ics in terms of improvements in kidney function after an
ages, and comparisons between groups were performed with episode of AKI.
the chi-square or Fisher exact test as appropriate. The
Shapiro–Wilk test was performed to assess data distribution;
Secondary outcomes
continuous variables are summarized as the means ± stan-
dard deviations (SD) if the data were normally distributed or The results of the secondary outcomes are shown in Table 2
medians and interquartile ranges (25–75th) if the data were and Figure 3. Among all patients, 45 (49%) died during the
4 J. S. CHÁVEZ-ÍÑIGUEZ ET AL.

Figure 1. CONSORT Flow diagram.

study, including 18 (37%) in the probiotic group and 27 confirming that the decrease was greater with probiotics
(61%) in the placebo group, which indicated that probiotic (between subjects p value = 0.04) (Table 2, Figure 3B).
treatment was favorable with a relative risk (RR) of 0.61 (95% Urinary volume (ml/day) increased from 1,000 (500–1,500)
CI 0.39–0.94, p = 0.02). Kaplan–Meier survival analysis on day to 1,100 (750–1,400) in the intervention group (p = 0.65) and
180 showed a hazard ratio (HR) of 0.56 (95% CI 0.32–1.04 from 1,095 (600–1,400) to 1,750 (1,200–2,300) in the placebo
p = 0.06) (Figure 3A). Causes of death were similar between group (p = 0.05), with a significant difference between the
the groups, with sepsis being the most common (39%), fol- groups (Table 2, Figure 3C).
lowed by cancer/neoplasia (13%) or cardiorespiratory (11%), The patients were followed for a median of 382 days
hematological (9%), gastrointestinal (9%) and neurological (193–967), and it was observed that their renal function
(6%) disease. deteriorated, which was based on an overall eGFR of 39 (23–
A total of 17 (19%) patients required KRT during the study 94 mL/min/1.73 m2). The eGFR was 46 (23–99 mL/min/1.73
follow-up period, which was mostly due to uremia, volume m2) in the probiotic group and 33 (24–59 mL/min/1.73 m2) in
overload, and electrolyte abnormalities; this included 12 the control group, meeting the criteria for CKD grade 3a and
(26%) in the probiotic group and 5 (12) in the placebo group, 3b, respectively, without a significant difference between
with an RR of 2.19 (95% CI 0.84–5.72, p = 0.11), as shown in groups (Table 2).
Table 2. In an exploratory multiple regression analysis, including
Additionally, urea levels (mg/dL) decreased significantly in baseline sodium and potassium levels, heart rate, diastolic
the probiotic group from 154 (70–173) to 80 (31–148), which blood pressure and stages KDIGO 3 in the model and weight-
was not observed in the placebo group, in which they only ing by group, the results for renal recovery and mortality
decreased from 130 (70–173) to 109 (53–160), (p = 0.09), remained nonsignificant, with p = 0.51 and 0.19, respectively.
 Renal Failure 5

Table 1. Study baseline characteristics according to the probiotics or placebo groups.

All (n = 92) Probiotics (n = 48) Control (n = 44) P
Age (years)—mean (SD) 56.9 ± 16.3 55.5 ± 16.7 58.4 ± 15.9 0.39
Female (%) 47 (51) 25 (52) 22 (50) 0.84
Comorbidities
Diabetes (%) 42 (46) 27 (56) 23 (52) 0.70
Hypertension (%) 38 (41) 20 (42) 18 (41) 0.94
Chronic kidney disease (%) 25 (27) 11 (23) 14 (32) 0.34
Chronic heart failure (%) 5 (5) 2 (4) 3 (7) 0.57
Cancer/neoplasia (%) 6 (6) 3 (6) 3 (7) 0.62
Hematological malignancy (%) 2 (2) 1 (2) 1 (2) 0.88
Gastrointestinal disease (%) 12 (13) 6 (12) (16) 0.74
 Neurological disease (%) 9 (6) 4 (8) 5 (11) 0.40
Baseline sCr (mg/dL) 1.1 (0.8–1.6) 1.1 (0.8–1.6) 1.1 (0.8–1.8) 0.82
Day 1
sCr, mg/dL—mean (IQR) 3.4 (2.3–5.0) 3.7 (2.3-–5.5) 2.9 (2.2–4.5) 0.26
 Urea, mg/dL—mean (IQR) 137 (81–187) 154 (83–189) 130 (70–173) 0.26
 Urinary volume, ml/day—mean (IQR) 1090 (500–1470) 1000 (500–1500) 1095 (600–1400) 0.87
Sodium, mEq/L—mean (SD) 135 ± 8.6 133 ± 9 136 ± 8 0.09
Potassium, mEq/L—mean (IQR) 4.4 (3.7–5.1) 4.5 (3.9–5.2) 4.1 (3.6–4.7) 0.19
Chloride, mEq/L—mean (SD) 102 ± 9.2 101 ± 9.4 103 ± 9.1 0.37
Calcium, mg/dL—mean (IQR) 7.8 (7.1–8.3) 7.7 (7.0–8.1) 7.9 (7.4–8.8) 0.22
pH—mean (DE) 7.33 ± 0.06 7.33 ± 0.06 7.33 ± 0.07 0.81
Bicarbonate, mmol/L—mean (SD) 19.1 ± 3.9 18.8 ± 3.9 19.6 ± 3.8 0.49
PCO2, mmHg—mean (IQR) 35 (29–40) 33 (30–40) 36 (29–44) 0.53
 Lactate, mmol/L—mean (IQR) 1.2 (0.9–1.6) 1.3 (0.9–1.6) 1.1 (1.0–1.4) 0.94
Hemoglobin, g/dL—mean (RIQ) 10.2 (8.6–12.0) 10.2 (8.4–11.7) 10.2 (8.9–12.5) 0.62
 Leucocytes, 103cél/µL—mean (IQR) 13.2 (9.3–17.9) 13.4 (9.9–18.4) 12.6 (9.1–17.6) 0.52
Platelets, 103cél/µL—mean (IQR) 212 (132–305) 212 (130–321) 194 (136–289) 0.82
Systolic blood pressure (mmHg) 110 ± 19 111 ± 19 109 ± 20 0.63
Diastolic blood pressure (mmHg) 65 (60–79) 60 (60–74) 70 (60–80) 0.16
Cardiac frequency (min) 85 (80–98) 90 (80–100) 82 (78–92) 0.19
Respiratory frequency (min) 20 (18–21) 20 (19–21) 20 (18–21) 0.60
KDIGO n,(%)
1 7 (7.6) 1 (2.1) 6 (13.6) 0.05
2 14 (15) 7 (14) 7 (16) 1.0
3 71 (77) 40 (83) 31 (70) 0.14
SOFA—mean (IQR) 6 (4–8) 6 (5–8) 5 (4–7) 0.43
Procalcitonin—mean (IQR) 9.3 (2.4–37.4) 8.1 (2.1–34.5) 12.7 (2.6–46.0) 0.76
Septic shock (%) 9.3 (2.4–37.4) 18 (37) 16 (36) 0.91

Table 2. Primary and Secondary objectives.

All (n = 92) Probiotics (n = 48) Control (n = 44) p RR
Primary Objective
Kidney function recovery—n (%)* 40 (43) 24 (50) 21 (48) 0.82 1.04
Secondary objective
Dead – n (%) 45 (49) 18 (37) 27 (61) 0.02 0.61
Kidney replacement therapy – n (%) 17 (19) 12 (26) 5 (12) 0.11 2.19
 Urea, mg/dL –mean (RIQ) 108 (148–232) 80 (31–148) 109 (53–160) 0.40
sCr – mean (IQR) 2.0 (0.8–2.8) 1.7 (0.7–3.2) 2.2 (1.2–2.7) 0.31
 Urinary volume, ml/día – mean (IQR) 1200 (900–1725) 1125 (750–1400) 1750 (1204–2375) 0.01
Potassium, mEq/L – mean (IQR) 4.0 (3.5–4.5) 4.0 (3.6–5.0) 4.0 (3.5–4.5) 0.52
Sodium, mEq/L – mean (SD) 136 ± 6.1 134 ± 5.9 137 ± 5.8 0.01
Chloride, mEq/L – mean (SD) 102 ± 7.8 101 ± 7.6 104 ± 7.7 0.16
pH – media (SD) 7.38 ± 0.11 7.35 ± 0.13 7.40 ± 0.07 0.18
Bicarbonate, mmol/L – mean (SD) 22.2 ± 4.7 21.6 ± 4.6 22.9 ± 4.9 0.45
Follow-up, days – mean (IQR) 382 (193–967) 642 (227–986) 370 (150–822) 0.20
Last eGFR/ml/min 1.73m2 – mean CKD-EPI (IQR) 39 (23–94) 46 (23–99) 33 (24–59) 0.45

Additional outcomes of interest bicarbonate levels, improved with increasing pH and bicar-
bonate during the study, with no difference between groups
Potassium levels decreased, and chloride levels increased
(Table 2, Supplemental Figure 2).
during the study in both groups, but they did not differ sig-
nificantly between intervention groups. Only sodium levels
decreased in the probiotic group (134 ± 5.9), and they
Adverse events
increased in the placebo group (137 ± 5.8) (p = 0.01). Calcium
values remained stable during the intervention, with no dif- The prespecified adverse events during the study period are
ferences between groups (Table 2, Supplemental Figure 2). presented in Table 3. A total of 53 patients were documented,
Acid–base status, which was assessed by serum pH and and gastrointestinal symptoms predominated. All were
6 J. S. CHÁVEZ-ÍÑIGUEZ ET AL.

Figure 2. Primary objective, kidney function recovery during the 7 days of the study trial.

considered mild, and they were similar between both groups role in the development and progression of CKD and was
of the study; none warranted suspending the interventions. even associated with an increased risk of dying [39]. In this
The probiotic group presented 34 adverse events; of these, 7 study, the lack of efficacy of probiotics in promoting KFR is
patients presented >2 events, and 27 presented only one difficult to contrast with other results since there have been
event. Abdominal distention was the most common, with 8 no other similar trials. However, previous experimental mod-
reported cases, followed by nausea and diarrhea, with 6 els have been encouraging. In mice induced to exhibit pyelo-
cases each. In the placebo group, 31 presented an adverse nephritis with E. coli injection, it was shown that the
event, 6 patients had >2, and the most common was diar- administration of Lactobacillus acidophilus and Bifidobacterium
rhea with 9 reported cases, there 7 cases of abdominal dis- before and after sepsis significantly improved renal function
tention, and 6 cases of vomiting. and attenuated inflammation and renal fibrosis [40]. Similarly,
administration of SCFAs improved renal function after AKI,
which was an effect mediated by the decrease in sCr and
Discussion
urea levels, and it also improved the percentage of necrosis
In this double-blind randomized clinical trial carried out in seen in kidney biopsies. These improvements were associated
patients with AKI secondary to sepsis, we found for the first with an attenuation of inflammation and significantly lower
time that the administration of probiotics for 7 days did not levels of IL-1b, IL-6, TNFα and MCP-1 [41]. The administration
improve KFR compared with placebo treatment, but it had a of Lactobacillus salivarius following cisplatin-induced AKI
trend to decrease the mortality rate, in addition to having an decreased the levels of markers of inflammation and severity
acceptable safety profile. scores on kidney histology [42] and, interestingly, maintained
KFR was observed in half of the patients in this study intestinal wall permeability, suggesting that it would prevent
during the 7-day period, which was similar to what was pre- bacterial translocation to the portal circulation and thereby
viously reported for patients with sepsis-induced AKI [36,37]. modulate systemic inflammation [43]. SCFA involvement has
In this clinical scenario, it is important to implement mea- also been implicated in AKI in humans; it was observed that
sures focused on improving kidney recovery within 7 days; if after AKI, the levels of D-amino acids and especially D-serine
this is not done, there is an increased risk of progression to increase, which are produced from SCFAs, suggesting a phys-
AKD, which increases the risk of developing de novo CKD or iological mechanism of protection against kidney insult [44].
CKD progression and increases the risk of cardiovascular We showed that the administration of probiotics tended
complications and death [37]. Recovery of kidney function to decrease mortality in rats. AKI related to sepsis has a poor
has been an unresolved issue for many years and has been prognosis. A meta-analysis reported that 45% of affected
recognized as a priority [38]; thus far, there is no available patients die during their stay in intensive care units and up
treatment that has consistently achieved this objective. to 49% die during hospitalization [45]; thus, it is extremely
It is plausible to think that uremic toxins derived from important to try to reduce these numbers. Probiotics have
intestinal dysbiosis promote kidney dysfunction and fibrosis, also been shown to decrease mortality in experimental mod-
a clear example is Trimethylamine-N-oxide (TMAO), a gut els. In rats with abdominal sepsis induced by cecal ligation,
microbial-dependent metabolite, plays a direct contributory it was shown that the administration of the probiotics
 Renal Failure 7

Figure 3. Secondary outcomes, A) Survival, B) serum urea, and C) urinary output, during the 7 days of the study trial.
8 J. S. CHÁVEZ-ÍÑIGUEZ ET AL.

Table 3. Adverse events during the 7 days of study period. demonstrated and have one of the worst adverse long-term
Probiotics (34) Placebo (31) prognoses [53–55].
Diarrhea 6 9 Considering the reported adverse events, we believe that
Abdominal distention 8 7 the administration of probiotics to patients with
Nausea 7 5
Vomiting 5 6 sepsis-induced AKI was well tolerated and had an acceptable
Rash 3 0 safety level. No adverse events were considered serious, and
other 5 4 none of the patients stopped treatment due to any adverse
events reported.
Lactobacillus rhamnosus and Bifidobacterium longum for For decades, different therapeutic agents have been inves-
7 days decreased the risk of dying by 40% [46]. The involve- tigated for the management of AKI associated with sepsis with
ment of intestinal dysbiosis and colon-associated uremic disappointing results; the use of agents such as statins [55],
toxin production in AKI patients was related to AKI severity erythropoietin [56], steroids [57], alkaline phosphatase [58] and
and an increased likelihood of dying [11]. Even in patients pirfenidone [17] is an important justified effort, and the search
with hospital-acquired AKI, it has been seen that the highest for a drug that consistently improves kidney function and
concentrations of uremic toxins generated from intestinal potentially decreases the probability of dying continues.
dysbiosis, such as indoxyl sulfate, were associated with an
almost 3-fold increase in the risk of dying [47], and a reduc- Limitations and strengths
tion in their levels improved AKI, as evaluated by the Risk,
Injury, and Failure; and Loss; and End-stage kidney disease Our results must be interpreted with caution, as this was a
(RIFLE) classification [35]. Our results indicate that a signifi- single-center study without an a priori calculation of sample
cant difference in mortality might be observable with an size due to the lack of literature to estimate an expected
increase in the number of cases and an extension of the minimal clinically important difference between groups; thus,
observation period. In other words, there is insufficient evi- a type II error cannot be ruled out; for instance, according to
dence to conclude that the administration of probiotics is the observed difference in the primary outcome between
not effective at this point. groups, the post hoc calculated power was 50% in our sam-
Regarding other parameters that have been used to evalu- ple, maintaining an α-error probability of 5%. There was also
ate renal function in patients with AKI, such as the need for a lack of measurements of the intestinal microbiota in feces,
KRT and sCr concentrations, we did not observe a positive as well as systemic inflammation parameters, and biomarkers
effect of the administration of probiotics. However, serum of renal tubular damage that reflect true kidney injury were
urea concentrations only improved significantly in the probi- not assessed. All patients were receiving antibiotics, which
otic group, not in the placebo group, although no significant may have impacted the probiotics administered. The study
differences were found between them. This effect could be population has concomitant pathologies such as CKD, DM,
explained by the modulation of intestinal dysbiosis with pro- sepsis, and a complex internal environment that could have
biotics and thus the attenuation of urea generation by intes- limited the effect of probiotics. We do not confirm that the
tinal bacteria [8], especially in the context of AKI associated absorption of probiotics has been optimal.
with sepsis [48]. Uremia and other colon-derived toxins have The strengths of the study lie in its design and the ade-
an impact on the KFR [35] and mortality [47]. The decrease in quate adherence of the patient groups to treatment; to our
urea levels in AKI has been the subject of debate for decades, knowledge, this is the first randomized control trial of AKI
but recent clinical trials have considered urea levels >240 mg/ septic patients treated with probiotics [10,34].
dL for the decision of when to start KRT in AKI patients (ELAIN In the next study regarding this topic, we suggest mea-
and AKIKI2 trials) [49,50]; thus, a decrease in urea levels could suring the microbiome between groups to quantify an actual
be relevant by delaying the start of KRT in certain scenarios. difference between those administered the probiotics vs pla-
The finding of higher urinary volume and serum sodium cebo, measure inflammatory markers given the speculation
levels in the placebo group than in the probiotics group around inflammation and immune regulation. Lastly, a larger
could be explained by the excretion of free water and thus and multicenter trial.
vascular decongestion. We believe this difference does not
profoundly impact the clinical course of these patients since Conclusion
urinary volume and sodium remained within ranges consid-
ered safe [51,52]. In AKI associated with sepsis, the administration of probiotics
It is important to comment on the values of eGFR for 7 days was safe, and compared with placebo, it did not
observed during the long-term follow-up of these patients improve renal function, but there was a trend toward
(∼1 year), which was 39 mL/min/1.73 m2, with no differences decreased mortality.
between the study groups, which means that they would be
classified as having CKD G3a, which implies a deterioration
Ethics approval and consent to participate
to almost half their baseline eGFR, which was ∼74 mL/
min/1.73 m2. The devastating sequelae in renal function after The study was approved by the Institutional Review Board
an episode of sepsis-induced AKI have been previously HCG/CEI-1342/18, was registered with the Clinical Trials
 Renal Failure 9

identifier NCT03877081, 03/15/2019 Informed consent was [6] Ramezani A, Raj DS. The gut microbiome, kidney dis-
obtained from all subjects. All methods were carried out in ease, and targeted interventions. J Am Soc Nephrol.
accordance with relevant guidelines and regulations. All 2014;25(4):657–670. doi: 10.1681/ASN.2013080905.
experimental protocols were approved by the Institutional [7] Pan W, Kang Y. Gut microbiota and chronic kidney dis-
Review Board ‘Comité de ética en Investigación del OPD ease: implications for novel mechanistic insights and
therapeutic strategies. Int Urol Nephrol. 2018;50(2):289–
Hospital Civil de Guadalajara Fray Antonio Alcalde’.
299. doi: 10.1007/s11255-017-1689-5.
[8] Ramezani A, Massy ZA, Meijers B, et al. Role of the gut
microbiome in uremia: a potential therapeutic target.
Authors’ contributions
Am J Kidney Dis. 2016;67(3):483–498. doi: 10.1053/j.
JSCI, MIE, AMG-G, ACH, RCD, GCA, were responsible for the ajkd.2015.09.027.
design, analysis and interpretation of the data. EMHB, ACRM, [9] Shimizu K, Ogura H, Asahara T, et al. Probiotic/synbiotic
FRA, MLPM, MPC, JATG, CPH, GNB, RMG, LAV, KRL and GGG therapy for treating critically ill patients from a gut mi-
were responsible for data collection. All authors have read crobiota perspective. Dig Dis Sci. 2013;58(1):23–32. doi:
and approved the manuscript. 10.1007/s10620-012-2334-x.
The preprint version of the manuscript was posted in May [10] Shimizu K, Ogura H, Hamasaki T, et al. Altered gut flora
30th, 2023 DOI: https://doi.org/10.21203/rs.3.rs-2820596/v1chrome- are associated with septic complications and death in
extension://efaidnbmnnnibpcajpcglclefindmkaj/https://assets. critically ill patients with systemic inflammatory re-
researchsquare.com/files/rs-2820596/v1/3db6af8a-624d-4728- sponse syndrome. Dig Dis Sci. 2011;56(4):1171–1177.
88fb-a3df924a6a4c.pdf?c=1689312580. doi: 10.1007/s10620-010-1418-8.
[11] Gisewhite S, Stewart IJ, Beilman G, et al. Urinary metab-
olites predict mortality or need for renal replacement
Disclosure statement therapy after combat injury. Crit Care. 2021;25(1):119.
doi: 10.1186/s13054-021-03544-2.
No potential conflict of interest was reported by the author(s). [12] Andrianova NV, Popkov VA, Klimenko NS, et al.
Microbiome-Metabolome signature of acute kidney
injury. Metabolites. 2020;10(4):142. doi: 10.3390/metabo
Funding 10040142.
This work was supported by the CONACYHT. [13] Emal D, Rampanelli E, Stroo I, et al. Depletion of gut
microbiota protects against renal Ischemia-Reperfusion
injury. J Am Soc Nephrol. 2017;28(5):1450–1461. doi:
Availability of data and materials 10.1681/ASN.2016030255.
[14] Chávez-Iñiguez JS, Villegas-Gutiérrez LY, Gallardo-González
Are available in the historical archive of the Hospital Civil AM. Acute kidney injury and intestinal dysbiosis. Front
Fray Antonio Alcalde. If any information is requested, please Nephrol. 2022;2:916151. doi: 10.3389/fneph.2022.916151.
contact Principal Investigator Dr. Jonathan Chávez-Iñiguez [15] Chávez-Íñiguez JS, Madero M. Global perspectives in
([email protected]). acute kidney injury: Mexico. Kidney360. 2022;3(4):737–
739. doi: 10.34067/KID.0006592021.
[16] Lombardi R, Ferreiro A, Claure-Del Granado R, et al.
ORCID EPILAT-IRA study: a contribution to the understanding
of the epidemiology of acute kidney injury in latin
Jonathan S. Chávez-Íñiguez http://orcid.org/0000-0003- america. PLoS One. 2019;14(11):e0224655. doi: 10.1371/
2786-6667 journal.pone.0224655.
[17] Chávez-Iñiguez JS, Poo JL, Ibarra-Estrada M, et al. Effect of
Prolonged-Release pirfenidone on renal function in septic
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