alexa Dose Escalation, Safety and Impact of a Strain-Specific Probiotic (Renadyl™) on Stages III and IV Chronic Kidney Disease Patients | OMICS International
ISSN: 2161-0959
Journal of Nephrology & Therapeutics

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Dose Escalation, Safety and Impact of a Strain-Specific Probiotic (Renadyl?) on Stages III and IV Chronic Kidney Disease Patients

Natarajan Ranganathan1*, Bohdan Pechenyak1, Usha Vyas1, Pari Ranganathan1, Stephanie DeLoach2, Bonita Falkner2, Alan Weinberg3, Subodh J Saggi4 and Eli A Friedman4

1Kibow Biotech Inc., Newtown Square, PA, USA

2Thomas Jefferson Univ., Philadelphia, PA, USA

3Mount Sinai School of Medicine, New York, NY, USA

4Downstate Medical Center, State University of NY, New York, NY, USA

*Corresponding Author:
Natarajan Ranganathan
Kibow Biotech, Inc. 4781 West Chester Pike
Newtown Square, PA 19073, USA
Tel: 610-353-5130
Fax: 610-353-5110
E-mail: [email protected]

Received Date: September 20, 2013; Accepted Date: October 25, 2013; Published Date: October 29, 2013

Citation: Ranganathan N, Pechenyak B, Vyas U, Ranganathan P, DeLoach S, et al. (2013) Dose Escalation, Safety and Impact of a Strain-Specific Probiotic (Renadyl™) on Stages III and IV Chronic Kidney Disease Patients. J Nephrol Ther 3:141. doi:10.4172/2161-0959.1000141

Copyright: © 2013 Ranganathan N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

The primary goal of the open label study of Renadyl™ in stage 3 and 4 chronic kidney disease patients was to confirm the safety and tolerability of several doses of Renadyl™ (90, 180, 270 billion colony forming units). Secondary goals were to quantify quality of life improvement, to confirm efficacy in reducing commonly known uremic toxins, and to investigate the effects on several biomarkers of inflammation and oxidative stress. Participants underwent physical examinations and venous blood testing, and completed quality of life questionnaires. Data were analyzed with SAS V9.2. Of 31 subjects, 28 (90%) completed the study (2 lost to follow-up). The primary goal was met, as no significant adverse events were noted during the dose escalation phase. All patients tolerated the maximum dose (note: 1 subject reported nausea upon initial use). The escalation efficacy was shown in statistically significant changes of serum creatinine (months 2 to 6: -0.23 mg/dL, p<0.05), C-reactive protein (months 2 to 6: -0.28 mg/L, p<0.05), and hemoglobin (base to month 6: 0.35 mg/dL, p<0.01, months 1 to 6: 0.46 mg/dL, p<0.001, months 2 to 6: 0.58 mg/dL, p<0.0001). Trends, but not statistical significance, were noted in blood urea nitrogen (base to month 4: -3.56 mg/dL, p<0.09; months 1 to 4: -3.81 mg/dL, p<0.07). The secondary goal was also met, as QOL measure of physical functioning improved (base to month 6, p<0.05) and a strong trend in reduction of pain was observed (base to month 6, p<0.08).

Keywords

Probiotics; Renadyl™; Dose escalation; Chronic kidney disease; Dysbiosis

Abbreviations

CKD: Chronic Kidney Disease; ESRD: End-Stage Renal Disease; QOL: Quality Of Life; CRP: C-Reactive Protein; BUN: Blood Urea Nitrogen; CFU: Colony Forming Unit; SHIME: Simulated Human Intestinal Microbial Ecosystem

Introduction

Probiotics are defined by the Food and Agriculture Organization (FAO) and World Health Organization (WHO) as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” (2002). Prebiotics, in turn, are defined as “non-digestible, but fermentable, foods/ingredients that allow specific changes, both in the composition and/or activity, in the gastrointestinal microflora that confers benefits upon host well-being and health [1]”. They now appear with increasing frequency in various foods, beverages, supplements, and are readily utilized in alternative and complementary medical practice strategies. Due to direct consumer advertising, the average population has been convinced of the positive role that probiotics play in health and disease. This has led to marketing and consumption of a number of probiotic supplements available for purchase online or in pharmacies without their benefit being scientifically proven in a rigorous clinical trial. The role of digestive [2] and immune [3] systems, as well as inflammatory [4] and oxidative stress [5,6] functions in the progression of kidney disease has been emphasized by researchers in the past decade. Current data have highlighted an integrated and perhaps a causal relationship between the observed clinical outcomes and the role of an activated immune system in uremia. Most recently, the June 2013 issue of this very publication included a review of the role of microbial imbalance (dysbiosis) in Chronic Kidney Disease (CKD), which discussed the extent to which the gut and its microbial population might play a permissive role in the generation or assist in the degradation (perhaps even both) of many of the uremic toxins [3]. The June issue’s cover was adorned by a hypothetical conceptualization of the relationship between a failing kidney and intestinal microbiota: the metabolic changes associated with the progression of CKD to End-Stage Renal Disease (ESRD) alter the balance of symbionts and pathobionts in a way that favors pathobiont overgrowth, i.e., dysbiosis. (Please see Figure 1 for further elucidation of dysbiosis).

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Figure 1: Dysbiosis in CKD.

Probiotic microbes are predominantly found in fermented dairy foods such as yogurt, kefir, cheese and other fermented foods. The expansion of our awareness and use of probiotics, however, has raced ahead of the scientific basis for the mechanisms by which they impact health. Probiotics are increasingly utilized in clinical settings. A simple search of the NIH clinicaltrials.gov registry for “probiotics” brought up 548 clinical studies [7]. As their safety and health benefits are established, it is reasonable to anticipate that probiotic bacteria will be incorporated into a growing number of clinical regimens, either on their own or as an adjunct/part of a combined treatment.

The National Institutes’ of Health (NIH) Human Microbiome Project (HMP) targeted a goal of sequencing the genome of the microbial ecosystem found in a healthy human body and, if possible, of defining a core microbiome [8-11]. This collaborative project provided an excellent opportunity to examine the microbial diversity within and across body habitats and individuals [12], and with regard to geography and age [13]. This was the first, extremely important step in a new research direction, which has the potential of revolutionizing the practice of medicine [14] and public health [15], as well as the very concept of who we are as human beings [16,17]. Unlike the human genome, the microbiome can be modulated and engineered, according to the therapeutic needs and diseased conditions [18,19]. The efficacy of microbiota-targeted therapies will need to be assessed using new diagnostic tools that measure community function rather than strictly microbial composition, including the temporal response of a microbial community to the introduction of external agents such as antibiotics or probiotics [20].

The human intestinal tract has been colonized by thousands of species of bacteria during the coevolution of man and microbes [21,22]. Gut-borne microbes outnumber the total number of cells in the human body by a factor of ten [23]. Recent metagenomic analysis of the human gut microbiota has revealed the presence of some 3.3 million genes, as compared to the mere 23 thousand known genes of the human body [24-26]. Microbial communities carry out the majority of the biochemical activity on the planet, and they play integral roles in metabolism and immune homeostasis in human physiology and function [27]. Evidence for various beneficial roles of the intestinal microbiota and, concomitantly, probiotic microbes in human health and disease has been expanding rapidly in recent years [28-31]. Beneficial impacts have been noted for gastrointestinal disorders [32-36] (incl. functional bowel disorders [37], inflammatory bowel disease and ulcerative colitis [38-41], diarrhea [42], and others), cardiovascular disorders [43-46], cancer [47-49], hepatic function [50], metabolic conditions (incl. diabetes [51-53], obesity [54-60], lipid metabolism [61,62]), neuropsychiatric disorders (depression and anxiety [63,64], chronic fatigue syndrome [65,66], autism [67-69], psychoneuroimmunity [70-72], and neurodermatology [73]), immune function [74-77] (incl. immunomodulation [78-81], inflammation [82,83], allergies [84], autoimmune disorders [85,86]).

In recent years, the general awareness of the rising global prevalence of kidney disease has been steadily growing among the medical and public health professionals [87-89]. Kidney disease is the eighth leading cause of death in the U.S. [90], with close to 600 000 ESRD patients (most of them on dialysis) and more than 20 million in earlier stages of CKD [91]. As the population continues to age and as the epidemiological shift from acute infectious to chronic metabolic diseases progresses, contributing factors to kidney disease such as obesity, diabetes and high blood pressure have spiraled out of control. People in the U.S. and globally are likely to have a major health crisis in kidney disease.

Over the past 15 years, Kibow Biotech has continuously explored the potential utilization of oral sorbents and probiotics as complementary strategy for CKD. The first patented and proprietary probiotic product formulation to maintain kidney health was developed-Kibow Biotics® (now Renadyl™, containing S. thermophilus KB 19, L. acidophilus KB 27 and B. longum KB 31 strains, a total of 30 billion Colony Forming Units (CFU) per capsule). It uses “enteric toxin removal technology” to specifically target and reduce several uremic toxins that diffuse from circulating blood across the bowel and contribute to CKD. Initial in vitro R&D lab studies were performed including the use of a Simulated Human Intestinal Microbial Ecosystem (SHIME), a fivestep biochemical reactor to mimic stomach, small intestine, ascending, transverse and descending colonic environments [92]. Further exploratory studies of orally administered probiotic bacteria were performed in 5/6th nephrectomized rats and minipigs [93,94], live cats [95] and dogs with diagnosed kidney failure, and in humans [96,97] with CKD and ESRD [98]. Human clinical trials included several pilotscale studies to determine whether daily treatment with probiotic bacteria would improve or delay the onset of established signs and symptoms of CKD.

Through all of the studies listed above, the Renadyl™ probiotic formulation has shown the ability to utilize various nitrogenous uremic toxins as nutrients for growth of the beneficial gut microbial population. In this manner, the specifically formulated probiotic microbial strains keep the uremic toxins from accumulating to highly toxic levels in patients with CKD. Unlike many untested probiotic supplements available on the market, Renadyl™ has the advantage of having proven scientific validity. In accordance with its mission to market only the scientifically proven products, Kibow Biotech opted to invest its resources into performing a rigorous clinical trial for specific clinical indication use in CKD, before initiating direct consumer marketing. In December of 2012, the most recent 6-month dose-escalation study in human subjects was completed (Figure 2). The primary goal was to confirm safety and tolerability of several doses of Renadyl™ (from 90 to 180 to 270 billion CFU). Secondary goals were to quantify Quality Of Life (QOL) improvement [99-107], to confirm the product’s ability to reduce the levels of commonly known uremic toxins, and to investigate the product’s effects on some inflammation and oxidative stress biomarkers.

nephrology-therapeutics-dose-escalation-design

Figure 2: Dose escalation study design.

Methods

Study design

An open label, dose escalation observational study of an orally administered, strain-specific probiotic formulation (Renadyl™) in CKD Stage 3 and 4 patients with compromised renal function was initiated at the Thomas Jefferson University (TJU) Nephrology Division in Philadelphia, PA, with the enrollment of the first patient in August of 2011. The study was approved by the Institutional Review Board of TJU and written informed consent was obtained from each participant at enrollment. The participants in the study enrolled voluntarily and were prequalified and selected based on prior medical history and the inclusion/exclusion criteria. TJU Institutional Review Board approved this clinical study protocol and a summary is recorded in the NIH registry www.clinicaltrials.gov (Trial #NCT01450657). Primary endpoints were defined as measurable improvement in the levels of biochemical markers, such as urea and creatinine, in hematological values (CBC) and in hepatological function. Secondary endpoints included the measurements of Quality Of Life (QOL) parameters in accordance with modified SF36 questionnaire. Finally, tertiary endpoints were measurements of the exploratory biomarkers of inflammation and oxidative stress (indoxyl sulfate, p-cresyl sulfate, serum pentosidine, β-2 microglobulin).

During the screening (T0), each patient was examined and the baseline values were obtained, after which the patient was initiated on the dose of 1 capsule containing 30 billion CFU thrice daily with meals (90 billion CFU/day). (Please refer to Figure 2 for the timeline of the study.) At the end of month 1 (T1), the dose was increased to 2 capsules (180 billion CFUs/day), and at month 2 (T2) – to the maximum of 3 capsules (270 billion CFUs/day) thrice daily with meals. At each visit, participants underwent routine physical examinations and blood draws, as well as were given modified SF-36 QOL questionnaires to complete and were monitored for compliance with the study protocol. The only exception was visit 3 (T3), where no physical examinations or blood draws were performed – only a QOL questionnaire and compliance monitoring were administered. After two months on the maximum dose (T3 and T4), the treatment was discontinued (T4) and the washout period began. Two months later, each patient came for the follow-up visit (T5) and completed the study.

Inclusion and exclusion criteria

The inclusion criteria defined the potential participant population as those between 18 and 75 years of age, diagnosed with CKD stages III or IV (pre-ESRD, stable for at least a year) and with serum creatinine levels greater than 2.5 mg/dL at the time of screening.

The exclusion criteria limited the study population by excluding (1) pregnant or nursing women, (2) those with HIV/AIDs or liver disease diagnoses, (3) those with active dependency on controlled substances and alcohol, (4) those on anticoagulant therapy regimen, (5) those refusing to sign the informed consent form, and (6) those with social conditions or medical debilitating disease/disorder, which, in the judgment of the investigator, would interfere with or serve as a contraindication to adherence to the study protocol or ability to give informed consent or affect overall prognosis of the patient.

Laboratory methods: biochemistry and hematology

Complete blood counts and serum biochemical testing were performed at the Nephrology Division of Thomas Jefferson University. The conversion of serum creatinine level to eGFR data was not considered important, since this study was a short-term 6-month study-a period that is too short for interpreting the eGFR data. Glucose was closely monitored, if the patient was diabetic.

While most blood tests were performed at the hospital, blood serum samples were also obtained and analyzed by Kibow’s laboratory for biochemical markers of inflammation and oxidative stress. Serum pentosidine and β-2 microglobulin were analyzed using ELISA kits obtained, respectively, from Novateinbio (catalog number NB-E10646) and R&D systems (Catalog number DBM200). Indoxyl sulphate and p-cresyl sulphate were quantified by HPLC on a Waters Alliance 2695 using published method of Niwa [108] and Meyer [109]. In addition, fecal samples were also obtained and analyzed at Kibow’s lab for the presence of the three strains comprising the formulation in Renadyl™ using microbiological methods of plating, enumeration and counting the colonies on appropriate and specific growth media on agar plates.

Statistical methods

All data were analyzed by Dr. Alan Weinberg, an Associate Professor of Biostatistics at the Mount Sinai School of Medicine, using SAS system software V 9.2 (SAS Institute Inc., Cary, NC). All variables – phenol, p-cresol, indoxyl sulfate, BUN and creatinine – were measured over five time points. These repeated measures were each modeled via the PROC MIXED procedure in SAS, similar to an analysis of variance for repeated measures.

Due to the fact that repeated measurements within each patient may be correlated, the Mixed Model procedure allows one to model this “correlation structure”, commonly referred to as a covariance pattern. This accurate estimate will allow for improved estimates of the standard errors of measurement, and therefore more powerful tests.

There are a number of various covariance structures to choose from. Three of the more common covariance structures include “Compound Symmetry” (CS), for correlations that are constant for any two points in time, “Auto-Regressive Order One” (AR1), for correlations that are smaller for time points further apart, and “Unstructured” (UN), which has no mathematical pattern within the covariance matrix. Other covariance structures that are usually tested include the Toplitz (TOEP) and the Heterogeneous Compound Symmetry Structure (CSH).

A likelihood ratio test or a procedure known as Akaike’s information criterion (AIC) [110] is used to discern which covariance pattern allows for the best fit. We therefore chose the “Compound Symmetry” (CS) structure. Adjusted means at each time point were then generated with adjusted standard errors. P values were not adjusted for multiple comparisons and the inflation of the Type I error.

Results

Out of 31 participants, 28 (90%) completed the study, with additional 2 participants lost to the follow-up. No significant adverse events were noted with dose escalation. All patients tolerated the maximum dosage, with the exception of patient CK020, who reported nausea upon initial use (see Adverse Events section). All study results are presented in Tables 1-4 and Figures 3 through 8. Statistically significant changes were observed in creatinine (Figure 4) (months 2 to 6: -0.23 ± 0.09 mg/dL, p<0.05), C-Reactive Protein (CRP) (mos. 2 to 6: -0.28 ± 0.14 mg/L, p<0.05), hemoglobin (baseline to month 6: 0.35 ± 0.13 mg/dL, p<0.01, months 1 to 6: 0.46 ± 0.13 mg/dL, p<0.001, months 2 to 4: 0.35 ± 0.13 mg/dL, p<0.01, months 2 to 6: 0.58 ± 0.13 mg/dL, p<0.0001) and hematocrit (baseline to month 6: 1.17%, p<0.05, months 1 to 4: 1.00%, p<0.05, months 1 to 5: 1.69%, p<0.001, months 2 to 5: 1.36%, p<0.005). In addition, trends not reaching statistical significance were observed in BUN (baseline to month 4: -3.56 ± 2.07 mg/dL, p<0.09; months 1 to 4: -3.81 ± 2.07 mg/dL, p<0.07), potassium (months 1 to 6: 0.21 ± 0.11 mmol/L, p<0.06, months 2 to 6: 0.19 ± 0.11 mmol/L, p<0.09), hemoglobin (baseline to month 2: 0.23 ± 0.13 mg/ dL, p<0.08, months 1 to 4: 0.23 ± 0.13 mg/dL, p<0.09, months 4 to 6: 0.23 ± 0.13 mg/dL, p<0.09) and CRP (baseline to month 2: 0.23 ± 0.14 mg/L, p<0.095). QOL results (Tables 3 and 4, Figures 6 and 8) indicated improvement in physical functioning (baseline to month 6, p<0.05), a trend toward reduction of pain (baseline to month 6, p<0.08), with no significant change in mental, emotional and social well-being.

  Month N Mean Std Dev Min Max
  0 28 48.82 17.91 16.00 88.00
  1 28 49.07 20.02 13.00 100.00
BUN 2 28 45.96 19.95 15.00 107.00
  4 27 44.85 14.72 14.00 72.00
  6 26 46.50 17.63 15.00 80.00
  0 28 2.38 0.86 1.20 4.60
  1 28 2.38 0.82 1.10 4.20
Creat. 2 28 2.31 0.91 0.90 4.00
  4 27 2.29 0.89 1.00 4.10
  6 26 2.51 1.13 1.00 6.20
  0 27 0.44 0.48 0.10 2.30
  1 2 0.20 0.28 0.00 0.40
CRP 2 2 0.15 0.21 0.00 0.30
  4 25 0.40 0.33 0.10 1.20
  6 25 0.50 0.48 0.10 1.90
  0 28 10.79 1.42 8.40 14.60
  1 28 10.68 1.53 8.30 14.70
HGB 2 28 10.55 1.39 8.20 13.70
  4 27 10.93 1.50 8.10 14.10
  6 26 11.06 1.40 9.10 14.50
  0 27 4.52 0.82 2.60 5.90
  1 28 4.56 0.75 2.70 5.90
K 2 28 4.54 0.72 3.10 6.00
  4 27 4.44 0.74 2.60 6.50
  6 26 4.39 0.45 3.50 5.20

Table 1: Clinical Lab Data - The MEANS Procedure.

  Months Estimate Std. Error DF t value Pr > |t|   Months Estimate Std. Error DF t value Pr > |t|
  0 to 1 -0.2500 2.0477 105 -0.12 0.9031   0 to 1 5.55x10-17 0.08810 105 0.00 1.0000
  0 to 2 2.8571 2.0477 105 1.40 0.1659   0 to 2 0.06071 0.08810 105 0.69 0.4923
  0 to 4 3.5557 2.0710 105 1.72 0.0889   0 to 4 0.05658 0.08911 105 0.63 0.5268
  0 to 6 1.9326 2.0958 105 0.92 0.3586   0 to 6 -0.1682 0.09018 105 -1.87 0.0649
BUN 1 to 2 3.1071 2.0477 105 1.52 0.1322 Creat. 1 to 2 0.06071 0.08810 105 0.69 0.4923
  1 to 4 3.8057 2.0710 105 1.84 0.0689   1 to 4 0.05658 0.08911 105 0.63 0.5268
  1 to 6 2.1826 2.0958 105 1.04 0.3001   1 to 6 -0.1682 0.09018 105 -1.87 0.0649
  2 to 4 0.6986 2.0710 105 0.34 0.7365   2 to 4 -0.00413 0.08911 105 -0.05 0.9631
  2 to 6 -0.9245 2.0958 105 -0.44 0.6600   2 to 6 -0.2290 0.09018 105 -2.54 0.0126
  4 to 6 -1.6231 2.1194 105 -0.77 0.4455   4 to 6 -0.2248 0.09120 105 -2.47 0.0153
  0 to 1 0.1811 0.1356 49 1.33 0.1881   0 to 1 0.1071 0.1284 105 0.83 0.4057
  0 to 2 0.2311 0.1356 49 1.70 0.0948   0 to 2 0.2321 0.1284 105 1.81 0.0734
  0 to 4 0.02527 0.04630 49 0.55 0.5877   0 to 4 -0.1182 0.1298 105 -0.91 0.3647
  0 to 6 -0.04454 0.04630 49 -0.96 0.3408   0 to 6 -0.3527 0.1314 105 -2.68 0.0084
CRP 1 to 2 0.05000 0.1638 49 0.31 0.7615 HGB 1 to 2 0.1250 0.1284 105 0.97 0.3323
  1 to 4 -0.1558 0.1358 49 -1.15 0.2569   1 to 4 -0.2253 0.1298 105 -1.74 0.0855
  1 to 6 -0.2256 0.1358 49 -1.66 0.1031   1 to 6 -0.4599 0.1314 105 -3.50 0.0007
  2 to 4 -0.2058 0.1358 49 -1.52 0.1361   2 to 4 -0.3503 0.1298 105 -2.70 0.0081
  2 to 6 -0.2756 0.1358 49 -2.03 0.0479   2 to 6 -0.5849 0.1314 105 -4.45 <0.0001
  4 to 6 -0.06981 0.04769 49 -1.46 0.1496   4 to 6 -0.2345 0.1329 105 -1.77 0.0805
  0 to 1 -0.04319 0.1106 104 -0.39 0.6970              
  0 to 2 -0.02177 0.1106 104 -0.20 0.8444              
  0 to 4 0.09543 0.1119 104 0.85 0.3956              
  0 to 6 0.1699 0.1132 104 1.50 0.1363              
K 1 to 2 0.02143 0.1094 104 0.20 0.8451              
  1 to 4 0.1386 0.1106 104 1.25 0.2130              
  1 to 6 0.2131 0.1119 104 1.90 0.0597              
  2 to 4 0.1172 0.1106 104 1.06 0.2919              
  2 to 6 0.1917 0.1119 104 1.71 0.0898              
  4 to 6 0.07449 0.1132 104 0.66 0.5119              

Table 2: Clinical Lab Data - Differences of Least Squares Means.

  Month N Mean Std Dv Min Max
  0 23 60.27 24.46 10.00 100.00
Physical Function 4 23 69.01 25.49 20.00 100.00
  6 23 71.16 24.94 20.00 100.00
  0 23 36.20 27.02 0 87.50
Pain 4 23 33.91 29.91 0 100.00
  6 23 26.63 23.39 0 77.50

Table 3: Quality of life – The MEANS Procedure.

  Months Estimate Std. Error DF t value Pr > |t|
  0 to 4 -8.7379 4.9615 44 -1.76 0.0852
Physical Function 0 to 6 -10.8877 4.9615 44 -2.19 0.0335
  4 to 6 -2.1498 4.9615 44 -0.43 0.6669
  0 to 4 2.2826 5.1966 44 0.44 0.6626
Pain 0 to 6 9.5652 5.1966 44 1.84 0.0724
  4 to 6 7.2826 5.1966 44 1.40 0.1681

Table 4: Quality of life – Differences of Least Squares Means.

nephrology-therapeutics-blood-urea-nitrogen

Figure 3: Blood Urea Nitrogen – Means by visit.

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Figure 4: Creatinine – Means by visit.

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Figure 5: C-reactive protein – Means by visit.

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Figure 6: Hemoglobin – Means by visit.

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Figure 7: Potassium – Means by visit

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Figure 8: Quality of life data – Means by visit.

CRP was not measured in months 1 and 2 (T1 and T2, please refer to Figure 2), with the exception of the first two patients. These two patients’ data from T1 and T2 were included in our statistical analysis. As the graph of CRP means in Figure 5 shows, this inclusion suggests that between months 2 and 4, when the patients were on the highest dose of Renadyl™, the levels of CRP actually increased. However, it would be more accurate to compare baseline and month 4 values, as they represent the data from all patients. If such comparison is made, it indicates that the mean value of CRP decreased slightly between baseline and month 4, and then started to rise during the washout period, when Renadyl™ supplementation was withdrawn.

Patient baseline demographics and epidemiology

Among the 28 participants that completed the study, the average age was 58 (range 22-77), the predominant sex was female (n=18, 64.3%). Systolic blood pressure (BP) averaged at 133 mmHg (range 110-190 mmHg), diastolic BP – 71 mmHg (50-100 mmHg), and pulse – 72 min (50-92 min). Most patients’ medical history included at least one of the following conditions: hypertension (n=23, 82.1%), diabetes (n=12, 42.9%, one of them borderline), dyslipidemia (n=18, 64.3%, includes hypercholesterolemia – 11, hypertriglyceridemia – 1, and hyperlipidemia – 6), and anemia (n=11, 39.3%). In addition, a sizeable proportion of the population exhibited such conditions as gastric esophageal reflux disorder (GERD, n=8, 28.6%), gout (n=5, 17.9%) and (auto) immune disorders (n=9, 32.1%, including allergic rhinitis – 3, seasonal allergies – 3, lupus – 2, asthma – 3, sarcoidosis – 1). A minority of participants also exhibited potassium imbalance (hyperkalemia – n=3, 10.7%; hypokalemia – n=1, 3.6%) Figure 7, endocrine dysregulation (hyperpara-/hypothyroidism – n=3 each, 10.7%), polycystic kidney disease (PKD, n=3, 10.7%), or glomerulonephritis (n=3, 10.7%). All medications, prescribed and administered to each patient prior to the initiation of the study and the Renadyl™ regimen, were either continued without change or reassessed and substituted by an alternative therapeutic modality, in accordance with the accepted standards of care.

Adverse events

The study was monitored according to the best clinical practices as per the nephrology institutional clinical standards of Thomas Jefferson University, Philadelphia, PA. With one exception, most events were judged as non-serious, not related to the study, and non-severe. The one exception was a patient who experienced mild nausea after starting on the study formulation. In all cases, appropriate actions were taken to resolve the underlying condition, to the best of the clinical staff’s abilities. One of the patients was taken off the study formulation for one week, when experiencing sore throat symptoms. One patient failed the inclusion criterion 3. Another patient was admitted to a hospital on June 8th, 2012, diagnosed with congestive heart failure, and subsequently discharged on June 15th. Following this episode, the patient decided to withdraw from the study due to the required multiple cardiologist visits, involving blood draws each time. This patient did not want to also have blood drawn at study visits, because the concept appeared overwhelming. Thus, a total of three patients out of thirty one who enrolled did not complete the study.

Discussion

Analysis of the study cohort indicated that administration of the probiotic mixture induced statistically significant improvements in serum creatinine, C-reactive protein, hemoglobin, hematocrit and physical functioning. Trends toward reduction were noted in the levels of BUN, potassium, hemoglobin, CRP and pain.

Toxicity due to the accumulation of various uremic toxins is a concern for CKD and ESRD patient populations. Concentrations of uremic solutes have been shown to increase as the disease progresses from CKD to ESRD [99]. The European Toxin workgroup (EUTOX) has classified many uremic toxins based on their molecular weights and their protein binding property [100]. Though urea is generally nontoxic, it can degrade to the highly toxic cyanate, which, in turn, binds to proteins by carbamylation, including serum albumin, and modifies them. Recent studies by Berg et al. [101]. Have shown that carbamylated serum albumin is a risk factor for mortality in patients with kidney failure. As early as 1998, it was shown that CKD patients are at a higher risk of cardiovascular problems. Death due to cardiovascular disease is higher by 10 to 20 times in these patients as compared with the general population [102]. Therefore, some believe it to be necessary to reduce the levels of urea in chronic renal failure patients by medication or other interventions and strategies, such as a probiotic therapy (some representatives of the lactic acid bacteria population have the capacity to metabolize urea).

Probiotics and prebiotics have been reported to enhance intestinal health for centuries [103]. Scientific proof has now been obtained that confirms their positive effects on human health in general [104]. Recently, the application of probiotics in various diseases has intensified, as understanding of how the gut microbiota shapes human health and how their composition changes in unhealthy populations is gained through extensive research efforts [105].

Our previous multicenter trials in patient cohorts with CKD stages 3 and 4 showed that the concentrations of uremic toxins – principally urea, uric acid and creatinine – were reduced, when the study subjects were treated with Kibow Biotics® (now Renadyl™) at a dose of 90 billion CFU per day [97]. The present study was conducted to assess the safety of Renadyl™ in a dose escalation regimen. As the results show (Figure 3), the levels of urea started decreasing as the patients began taking Renadyl™. These levels decreased until month 4, indicating that the probiotic formulation could reduce the toxic levels of urea. Upon discontinuation, after a two-month washout period, the urea concentrations increased again, indicating that it was indeed the bacterial strains in Renadyl™ that were able to metabolize urea.

Recent studies accomplished at Stanford University have indicated that metabolites that are also uremic toxins, such as phenol and indoles, come from colonic fermentation [106]. In CKD, protein digestion is impaired. Undigested proteins enter the large intestine and are fermented by pathogenic bacteria, thus leading to the formation of indoles and phenols, which are sulphated and converted to indoxyl and p-cresyl sulphates. Studies by Vaziri et al. have shown that renal failure patients have an imbalanced gut microflora [107].

This study investigated whether Renadyl™ supplementation could lower the concentrations of these putrefactants. Indoles, for example, are produced from amino acid tryptophan, and the administration of probiotics might be able to alter their generation rates. Although indole generation tended to decrease in this study, the results varied widely and did not reach statistical significance (data omitted). The reason for this variation could have been the suboptimal procedure, which necessitated obtaining the samples from the study site at Thomas Jefferson University and subsequently conducting assays in the Kibow’s laboratory. Performing all laboratory analyses on the study site would have been optimal in a clinical study such as this, to avoid unnecessary time lapses and factors related to transportation.

Study limitations

The most significant limitation was sample size, affecting the statistical power of the study results. Due to the prohibitive costs associated with conducting clinical trials, a larger sample size was not feasible to attain under this particular study design. To confirm the results, especially those trends not reaching the level of statistical significance, a study with a larger sample size is warranted. Other limitations included the laboratory arrangements – clinical samples for inflammatory/oxidative stress marker analysis were delivered after long periods of storage, therefore not fresh. This may be one of the reasons for highly variable and inconsistent results that preclude any conclusions.

No major issues were encountered with regard to patient adherence with the treatment regimen. Average adherence amounted to 94%, with a standard deviation of 17%.

Conclusions

Administration of Renadyl™ for 4 months in CKD Stage 3 and 4 patients, reaching the highest dose of 270 CFUs per day, appears safe and well-tolerated. Statistically significant improvements were noted in creatinine, C-reactive protein, hemoglobin, and physical functioning. Trends toward reduction were noted in BUN and pain. Other markers of inflammation and oxidative stress exhibited a lot of variation. The study did not have sufficient statistical power to ascertain changes in other molecular toxins.

Disclosure

Kibow Biotech Inc., a privately owned biotechnology company focused on probiotics, financed this clinical investigation at the Thomas Jefferson University. Part of the data was also obtained in Kibow’s own fully equipped research laboratories.

Prior Abstract Publication

A preliminary analysis of an incomplete data set from this trial (n=24) was presented in May 2013 as a poster at the World Congress of Nephrology in Hong Kong. A preliminary analysis of the completed data set (n=28) was presented in June 2013 at the conference “Probiotics, Prebiotics, and the Host Microbiome: The Science of Translation” at the New York Academy of Sciences.

Sources of Support

The study was performed at the Thomas Jefferson University and was funded by Kibow Biotech, Inc.

References

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