Clinical and experimental use of probiotic formulations for management of end-stage renal disease: an update Alessandro Di Cerbo, Federica

Pezzuto, Lucia Palmieri, Valentina Rottigni, Tommaso Iannitti & Beniamino Palmieri
International Urology and Nephrology ISSN 0301-1623 Int Urol Nephrol DOI 10.1007/s11255-012-0335-5

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Int Urol Nephrol DOI 10.1007/s11255-012-0335-5

NEPHROLOGY - REVIEW

Clinical and experimental use of probiotic formulations for management of end-stage renal disease: an update
Alessandro Di Cerbo Federica Pezzuto Lucia Palmieri Valentina Rottigni Tommaso Iannitti Beniamino Palmieri

Received: 28 July 2012 / Accepted: 9 November 2012 Springer Science+Business Media Dordrecht 2013

Abstract Nowadays kidney transplantation and dialysis are the only available therapies for end-stage renal disease management. They imply a considerable increase in plasma concentration of uremic wastes including creatinine, urea and uric acid. These invasive procedures impose high social costs that prevent many low-income countries from adequately treating the patients affected by renal insufciency. For years, many studies on uremic waste removal through the gut lumen have been published with conicting results. More recently, microencapsulation of probiotic bacteria has been performed by different research groups. This evidence has opened a new perspective on therapeutic modication of gut bacterial ora in the context of renal disease. This review gives an overview of the experimental and clinical use of probiotic formulations in the context of end-stage renal disease.

Keywords End-stage renal disease Microencapsulation Probiotics Dialysis Kidney stones Bacteria Chronic kidney disease

End-stage renal disease End-stage renal disease (ESRD) is the last stage of chronic kidney disease (CKD) [1] and is characterized by a glomerular ltration rate (GFR) fall below 15 ml/ min/1.73 m2 [2]. Based on 2012 report from United States Renal Data System (USRDS), the rate of new ESRD cases per million population was 348 in 2010 [3].

Probiotics
A. Di Cerbo F. Pezzuto V. Rottigni B. Palmieri Department of General Surgery and Surgical Specialties, Surgical Clinic, University of Modena and Reggio Emilia Medical School, Modena, Italy L. Palmieri Nephrology and Dialysis Division, University of Modena, Modena, Italy T. Iannitti (&) Department of Physiology, School of Medicine, University of Kentucky Medical Center, Lexington, KY 40536-0298, USA e-mail: tommaso.iannitti@gmail.com

Over 2,000 species of commensal bacteria live in the human body, the majority of which are in the intestinal tract where they are in a natural balance, namely symbiosis [4]. Among probiotic bacteria belonging to the intestinal ecosystem, bidobacteria (gram-positive, anaerobes and irregular rod-shaped) are the most abundant and potentially enhance humoral and cellular immune response against antigens [57]. The gut probiotic population is reduced during antibiotic administration and with age, when pathogenic ora increases [8]. For example, lyophilized

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Bidobacterium bidum and Lactobacillus acidophilus signicantly reduced colonic inammatory inltration, without altering T, B and Leu7? cell percentage in a cohort of patients aged over 70 [9]. At the same time, a signicant increase in peripheral blood B cell frequency was also noted. Probiotics also target the bowel immune response through dendritic cell and natural killer cell activity or pro-inammatory cytokine production and modulation (down-regulation of TNF-a and IL-8 and inhibition of NFjB activation) [1014]. Moreover bidobacteria decrease ammonia and excess cholesterol in the blood [15, 16]. The probiotics Lactobacillus bulgaricus, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Streptococcus faecium and Streptococcus thermophilus also assist lactose enzymatic digestion and lipolytic digestive activity with cholesterol-lowering effects.

develop kidney stones in ERSD patients is around 51 % [31]. Furthermore, a large clinical study showed a graded association between episodes of kidney stones and risk of renal disease including ESRD [32]. About 80 % of kidney stones are made of calcium oxalate (CaOx), and urinary oxalate is the main risk factor accounting for this condition [33, 34].

Experimental studies of probiotics for management of kidney stones As a preventive therapeutic approach for kidney stones, a moderate use of oxalate-containing food such as beet, chard, spinaches and cocoa powder, characterized by the highest oxalate levels, is required; however, a microbiological approach may also be effective [35, 36]. From an experimental perspective, a dose-dependent decrease in urinary oxalate was observed in rats affected by dietaryinduced chronic hyperoxaluria receiving Oxalobacter formigenes (a specic oxalate-degrading gramnegative anaerobe which lives in vertebrate gastrointestinal tract) by esophageal gavage [37]. An in vitro study assessed the oxalate-degrading ability of 31 lactobacilli in a selective medium showing that only Lactobacillus casei HY2743 and Lactobacillus casei HY7201 were able to degrade oxalate [38]. Building upon these ndings, an experimental study was conducted in stone-forming Srague-Dawley rats showing that treatment with Lactobacillus casei HY2743 and Lactobacillus casei HY7201 resulted in a decrease in urine oxalate excretion and less abundant crystals in kidneys, if compared to control group [38]. This study suggests an important role for lactobacilli as therapeutic agents for prevention of urinary stones. Another study also analyzed the ability of some Lactobacillus strains, isolated from the canine and feline gastrointestinal tract, to degrade oxalate in vitro, showing that several Lactobacillus animalis and Lactobacillus murinus isolates degraded ammonium oxalate. Lactobacillus animalis 223C, Lactobacillus animalis 5323, Lactobacillus murinus 1222 and Lactobacillus murinus 3133 were also tested in rats, showing that only the two Lactobacillus animalis strains were effective in reducing oxalate excretion, while all the four strains survived gastric transit [39].

ESRD pathophysiology and microbiome During ESRD, the uremic toxins, consisting in nitrogen waste products, cause an uremic condition inhibiting several physiological and biochemical functions [1720]. CKD is also characterized by an alteration in mineral metabolism resulting in a decrease in serum levels of calcium and activated vitamin D versus increased phosphorous and parathyroid hormone [21 24]. Chronic renal failure has been associated with small intestinal bacterial overgrowth (SIBO), a pathological state characterized by a competition between bacteria and the lumen host for nutrients introduced in the body through alimentation [2528]. In this situation, bacteria may also utilize intraluminal proteins in the small bowel that may lead to protein deciency and excessive production of ammonia by bacteria [29]. The gut microbiome, dened as the bacterial pool of the gut and its genome, undergoes dramatic changes during kidney insufciency, and harmful bacterial species are allowed to overgrow resulting in an imbalance in the probiotic microenvironment, affecting in particular lactobacilli and bidobacteria [30].

Role of kidney stones in ESRD Kidney stones have a high incidence rate worldwide. For example, in the USA, the risk to

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Clinical studies of probiotics for management of kidney stones Probiotics have already found application in the clinical setting for management of kidney stones. In fact, a 70 % reduction in stone formation has been reported in patients harboring Oxalobacter formigenes in the gut [40]. A study, involving six patients with CaOx urolithiasis and intermediate iperoxaluria ([40 mg/24 h), was designed to determine the efcacy of a lyophilized probiotic formulation to reduce oxaluria. They received a daily mixture containing Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus plantarum, Bidobacterium infantis and Streptococcus thermophilus for 4 weeks. A signicant reduction in 24-h oxalate excretion was observed in all 6 patients at the end of the study period and 1 month after the end of treatment. In vitro experiments revealed that Lactobacillus brevis grew into an oxalate-containing medium, but displayed a modest ability to degrade oxalate. On the other hand, Bidobacterium infantis not only grew rapidly in oxalatecontaining medium, but also showed a quite good ability to degrade oxalate. Lactobacillus acidophilus and Streptococcus thermophilus growth was inhibited by oxalate, and they displayed ability to degrade this metabolite [41]. A further study correlated for the rst time the presence of Oxalobacter formigenes in the gut with urinary oxalate levels in 35 patients affected by kidney stones compared to 10 healthy controls without a history of urolithiasis. When fecal samples were analyzed, only 26 % of these patients presented Oxalobacter formigenes, against a value of 60 % observed in controls. Although no signicant difference was found in terms of oxalate urinary excretion, among stone-formers, Oxalobacter formigenes-negative patients had signicantly higher urinary oxalate levels, if compared with subjects testing positive for this bacterium (41.7 vs. 29.4 mg/day). Moreover, all 10 hyperoxaluric stone-formers ([44 mg/day) tested negative for Oxalobacter formigenes [42]. In the year 2005, Lieske and co-workers studied the efcacy of a probiotic formula, OXADROP, (4 g per dose, VSL Pharmaceuticals), containing Lactobacillus acidophilus, Lactobacillus brevis, Streptococcus thermophilus and Bidobacterium infantis for oxaluria treatment. The different strains were mixed in a 1:1:4:4 ratio and prepared as a granulate. They were chosen based on their ability to degrade oxalate in vitro. Ten male and

female patients presenting hyperoxaluria ([0.5 mmol/ l/day; [45 mg/day) and gastrointestinal disorders (inammatory bowel disease in remission, celiac sprue, gastrointestinal resection resulting in short bowel syndrome or chronic pancreatitis) associated with fat malabsorption received increasing doses of OXADROP for a 3-month period. After a month, oxalate urinary excretion fell/remained stable in 7 out of 10 patients (19 % mean decrease from baseline) who received one dose of OXADROP per day. After 2 months, it was reduced by 24 % in 8 out of 10 patients (2 doses per day), but increased toward baseline levels in 4 patients after 3 months (3 doses per day; mean decrease of 2 % from baseline). Interestingly, a slight urinary oxalate mean decrease of 20 % was observed during the washout period, if compared to baseline [43]. On the other hand, OXADROP did not show efcacy in another study involving 20 patients affected by calcium stones and idiopathic hyperoxaluria [44]. Ferraz and coworkers tested the efcacy of a bacterial mixture composed of Lactobacillus casei and Bidobacterium breve to lower urinary oxalate in 14 stone-forming patients affected by hyperoxaluria while undergoing an oxalate-rich diet [45]. This mixture showed a variable lowering effect on urinary oxalate excretion. The efcacy of Oxalobacter formigenes in reducing the urinary oxalate excretion in primary hyperoxaluric patients has also been investigated. After 12 years post-treatment follow-up, bacterial gut colonization was not achieved in most of the patients involved in this study. Only in a patient, who showed colonization, the oxalate urinary excretion was normalized over time [46]. In summary, some probiotic bacteria have shown promise in managing hyperoxaluria and kidney stones warranting further investigation in larger clinical trials.

Experimental studies of probiotics in ESRD In vivo experimental studies have been conducted in rodents and felines to test the hypothesis of therapeutic probiotic administration for management of ESRD. For instance, a study was performed in 36 5/6th SpragueDawley nephrectomized rats, a model of chronic renal failure. They were divided into ve groups compared to a uremic control group and a nonuremic control group (non-nephrectomized rats). They were fed on a casein-based diet and Bacillus pasteurii

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(group 1), Sporolac (Lactobacillus sporogenes; group 2), Kibow cocktail (Lactobacillus acidophilus, Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus bidus, Lactobacillus casei, Lactobacillus reuteri, group 3), CHR Hansen Quarto (Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus bidus, Streptococcus thermophilus, group 4) and ECONORMTM (Saccharomyces boulardii, group 5). The two control groups received the same diet with no probiotic supplements. Bacillus pasteurii administration, as well as Sporolac supplementation enhanced survival of 5/6th nephrectomized rats, slowing down the progress of renal injury. These ndings support the idea of clinical efcacy of these bacterial strains for management of ERSD [47]. A further study, performed by the same research group, tested the non-pathogenic soil-borne alkaliphilic urease-positive bacterium Sporosarcina pasteurii for therapeutical purposes to mitigate uremia intoxication in 5/6th nephrectomized rats. Following daily administration of 10 CFU of live Sporosarcina pasteurii, a reduction in blood urea nitrogen levels was observed. Furthermore, this nding coupled with a signicantly prolonged lifespan of uremic animals [48]. In summary, contrasting results have been reported in animal studies on ESRD. Different animal species and probiotic strains used may account for these differences.

Clinical studies of probiotic administration to relieve uremia In recent years, many clinical studies have been performed to assess the efcacy of natural living or genetically-modied bacteria on uremic pathology that often develops in patients affected by ESRD [17 20]. For instance, 8 hemodialysis patients, treated with Lactobacillus acidophilus (NCFMTM), displayed a signicant decrease in dimethylamine and nitrosodimethylamine, two uremic toxins originating from the gut [49]. A further study assessed the effectiveness of 27.9 mg Lebenin (one capsule = Bidobacterium infantis 1 9 108, Lactobacillus acidophilus 1 9 108 and Enterococcus faecalis 1 9 108) administered in 20 patients twice a day for a month. After 2 weeks, fecal p-cresol and indican, but not phenol levels, were reduced. After 4 weeks, indican plasma levels significantly decreased from 212 40 to 147 25 nmol/

ml, while p-cresol decreased only slightly, although the fecal accumulation of such toxin resulted inhibited by Lebenin [50]. The therapeutic efcacy of 5-week administration of Bidobacterium longum in gastroresistant seamless capsule (3 9 109 CFU; Bina) versus bidobacteria in powder formulation (2 9 107 CFU; Lac B) on indoxyl-sulfate levels in 22 hemodialysis patients has also been tested. In this study, 11 patients received Bina capsules, while the remaining eleven subjects received Lac B. Indoxylsulfate serum levels were signicantly reduced in Bina-treated patients before undergoing dialysis (from 4.5 to 3.8 mg/dl), but not in patients treated with Lac B [51]. In the same year, Ando and coworkers administered Bidobacterium longum (Bidus HD)-enteric-coated capsules to 27 patients affected by chronic renal failure for a 6-month period. Although in the treated group no signicant variation in biochemical parameters was detected, an ESRD delay in patients with an initial serum creatinine concentration C4.0 mg/dl or inorganic phosphate concentration C4.0 mg/dl was achieved [52]. In the year 2010, Meijers et al. carried out a study to assess the efcacy of a 4-week escalating dose regimen of oligofructose-enriched inulin in 22 maintenance hemodialysis patients (Orafti Synergy 1 = a mixture of oligofructose and Raftiline HP; 10 g per sachet; Orafti, Tienen, Belgium). Probiotic administration signicantly reduced p-cresyl sulfate generation rates and serum concentrations in all hemodialysis patients [53]. A further study was conducted by Nakabayashi and coworkers to assess the efcacy of a synbiotic formulation (2 weeks, 3 times a day; SYN), containing Lactobacillus casei Shirota, Bidobacterium breve Yakult and galacto-oligosaccharides on p-cresol levels in 9 hemodialysis patients. Patients with a high serum p-cresol levels tended to have hard stools with difculty in defecation. Following SYN treatment, stool quantity increased signicantly, while hard, muddy or soft stools tended to be replaced by normal ones. The serum p-cresol levels also decreased signicantly [54]. In the context of CKD, in the year 2009, a Canadian study tested the clinical and biochemical efcacy of a probiotic mixture (KB = mixture of Lactobacillus acidophilus KB27, Bidobacterium longum KB31 and Streptococcus thermophilus KB19 for a total of 1.5 9 1010 CFU) administration in 13 stage 3 and 4 CKD patients over a 6-month period. During the treatment period, all

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patients showed a signicant decrease in mean BUN level, if compared with controls. On the other hand, uric acid levels signicantly increased, while serum creatinine levels did not change [55]. One year later, the same research group performed a 4 nation clinical trial in 46 stage 3 and 4 CKD patients who underwent treatment with KB probiotic mixture. All patients were monthly examined for 3 months [56]. Oral ingestion of KB was well tolerated and safe during the entire trial period at all sites. BUN levels decreased in 29 patients, creatinine levels decreased in 20 patients and uric acid levels decreased in 15 patients. Almost all subjects showed a perceived substantial overall improvement in their

quality of life and absence of serious adverse effects supporting the use of these probiotics for bowel-based toxic solute extraction. In summary, different clinical studies in hemodialysis/CKD patients suggest that administration of a single probiotic or a combination of bacterial strains improve biochemical parameters in these patients and result in a delay in ESRD as shown by Ando and co-wokers [52]. However, further studies comparing different probiotic strains and involving larger cohorts of patients are required to reach a nal conclusion. Experimental and clinical studies using probiotic formulations for treatment of ESRD and uremia, respectively, are summarized in Tables 1 and 2.

Table 1 Experimental studies of probiotic administration for treatment of ESRD Authors Ranganathan et al. [47] Design and treatment 36 5/6th SpragueDawley nephrectomized rats fed on a casein-based diet and Bacillus pasteurii (group 1), Sporolac (Lactobacillus sporogenes; group 2), Kibow cocktail (Lactobacillus acidophilus, Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus bidus, Lactobacillus casei, Lactobacillus reuteri, group 3), CHR Hansen Quarto (Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus bidus, Streptococcus thermophilus, group 4) and ECONORMTM (Saccharomyces boulardii, group 5) for 16 weeks 18 5/6th SpragueDawley nephrectomized rats fed with Sporosarcina pasteurii for 156 days Outcome Bacillus pasteurii and Sporolac supplementation enhanced survival of rats while slowing the progress of renal injury

Ranganathan et al. [48]

Daily reduction in BUN levels coupled with a signicantly prolonged lifespan

Table 2 Clinical studies of probiotic administration for treatment of uremia Authors Hida et al. [50] Takayama et al. [51] Ando et al. [52] Meijers et al. [53] Nakabayashi et al. [54] Ranganathan et al. [55] Ranganathan et al. [56] Design and treatment 20 uremic patients treated with 27.9 mg Lebenin for 4 weeks 11 hemodialysis patients treated with Bina and 11 patients treated with Lac B for 5 weeks 27 patients with chronic renal failure treated with Bidobacterium longum for 6 months 22 hemodialysis patients treated with escalating dose regimen of oligofructose-enriched inulin for 4 weeks 9 hemodialysis patients treated with SYN 3 times a day for 2 weeks 13 stage 3 and 4 CKD patients treated with a KB mixture for 6 months 46 stage 3 and 4 CKD patients treated with KB mixture for 6 months Outcome Indican plasma levels were signicantly decreased, while pcresol was only slightly decreased Indoxyl-sulfate serum levels were signicantly reduced in Bina-treated patients, but not in Lac B-treated subjects ESRD was delayed p-cresyl sulfate generation rates and serum concentrations were decreased Muddy or soft stools tended to be replaced by normal ones and serum p-cresol levels decreased signicantly BUN levels decreased while uric acid levels increased. No changes in serum creatinine levels were observed BUN levels decreased in 29 patients, creatinine levels decreased in 20 patients, and uric acid levels decreased in 15 patients. An improvement in quality of life was observed. No serious adverse events were noted.

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Conclusions During the past few years, the interest in therapeutic modication of gut bacterial ora for management of ERSD has gained growing attention. This review gives an overview of the experimental and clinical use of probiotic formulations in the context of ESRD. Experimental studies have focused on the efcacy of bacterial administration to improve kidney insufciency parameters and symptoms, resulting, at least in some cases, in a positive and promising outcome. On the other hand, clinical trials are still limited and do not involve a sufcient number of participants to draw a nal conclusion on the theraputic use of probiotics in ESRD. Clinical studies comparing different probiotic strains, will shed light on the probiotic strains with higher effectiveness for management of this condition.
Acknowledgments The authors contributed equally to this work. This review was not supported by grants. The authors thank Professor Decenzio Bonucchi (Nephrology division, Policlinico di Modena, Italy) for his precious advice. Conict of interest The authors certify that they have no conict of interest with any nancial organization regarding the material discussed in this manuscript.

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