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The use of antibiotics and risk of kidney stones
Abstract
Purpose of review:
The effect of the intestinal microbiome on urine chemistry and lithogenicity has been a popular topic. Here we review the evidence for exposure to antibiotics increasing the risk of nephrolithiasis.
Recent findings:
Studies of the intestinal microbiome have focused on Oxalobacter formigenes, an anaerobe that frequently colonizes the human colon. As a degrader of fecal oxalate its presence is associated with lower urinary oxalate, which would be protective against calcium oxalate stone formation. It also appears capable of stimulating colonic oxalate secretion. A recent study showed that antibiotics can eliminate colonization with O. formigenes. In a case-control study, exposure to sulfa drugs, cephalosporins, fluoroquinolones, nitrofurantoin/methenamine, and broad spectrum penicillins prospectively increased the odds of nephrolithiasis. The effect was greatest for those exposed at younger ages and 3-6 months before being diagnosed with nephrolithiasis.
Summary:
Recent evidence suggests a possible, causal role of antibiotics in the development of kidney stones. A possible explanation for this finding includes alterations in the microbiome, especially effects on oxalate-degrading bacteria like O. formigenes. Ample reasons to encourage antibiotic stewardship already exist, but the possible role of antibiotic exposure in contributing to the increasing prevalence of kidney stones in children and adults is another rationale.
... Recent findings have elucidated the relationship between antibiotic use and increased risk of kidney stones. Specifically, antibiotics may impact the intestinal microbiome, significantly regulating urinary oxalate levels [69]. The bacterium Oxalobacter formigenes helps degrade oxalate in the gut, reducing its absorption into the bloodstream and lowering urinary oxalate levels, thereby preventing the formation of calcium oxalate kidney stones [69]. ...
... Specifically, antibiotics may impact the intestinal microbiome, significantly regulating urinary oxalate levels [69]. The bacterium Oxalobacter formigenes helps degrade oxalate in the gut, reducing its absorption into the bloodstream and lowering urinary oxalate levels, thereby preventing the formation of calcium oxalate kidney stones [69]. However, certain antibiotics can disrupt the intestinal microbiome, including eliminating O. formigenes [69]. ...
... The bacterium Oxalobacter formigenes helps degrade oxalate in the gut, reducing its absorption into the bloodstream and lowering urinary oxalate levels, thereby preventing the formation of calcium oxalate kidney stones [69]. However, certain antibiotics can disrupt the intestinal microbiome, including eliminating O. formigenes [69]. Without this oxalate-degrading bacterium, there is an increased risk of elevated urinary oxalate levels, contributing to kidney stone formation. ...
Pediatric nephrolithiasis is an ancient and complex disorder that has seen a significant rise in recent decades and the underlying causes contributing to stone formation in children may also be shifting. Historically, kidney stones have been linked to factors such as metabolic disorders, congenital abnormalities, and family history. However, the recent increase in incidence appears to be associated with new risk factors, including changes in lifestyle and diet, the growing prevalence of obesity, metabolic syndrome, diabetes, and even climate change. Given this evolving landscape, performing a comprehensive metabolic evaluation during the diagnostic process is essential. A complete metabolic evaluation should thus be performed during the diagnostic assessment to identify any modifiable risk factors predisposing to stone recurrence and reduce the need for surgical management, extrarenal comorbidity, and the increased burden of care.
... It is little wonder that antibiotics would affect gut microbiota and reduce the number of ODB [19,20]. The evidence of antibiotics' effect on ODB was generally based on quantification before and after antibacterial treatment [19,20]. ...
... It is little wonder that antibiotics would affect gut microbiota and reduce the number of ODB [19,20]. The evidence of antibiotics' effect on ODB was generally based on quantification before and after antibacterial treatment [19,20]. It has been demonstrated that the administration of different antibiotic classes reduces ODB in the gut for a longtime period after antibiotic exposure [19][20][21]. ...
... The evidence of antibiotics' effect on ODB was generally based on quantification before and after antibacterial treatment [19,20]. It has been demonstrated that the administration of different antibiotic classes reduces ODB in the gut for a longtime period after antibiotic exposure [19][20][21]. However, the effect of antibiotics on total ODA in fecal microbiota has never been evaluated before. ...
The present study aimed (i) to evaluate whether ceftriaxone treatment could affect not only intestinal oxalate-degrading bacteria number but also their total activity to degrade oxalate and influence oxalate homeostasis in rats, (ii) and to estimate the ability of commercially available inulin-contained synbiotic to restore fecal oxalate-degrading activity and ceftriaxone-induced disruption of oxalate homeostasis in rats. Twenty-eight female Wistar rats (200–300 g) were randomly divided into four groups (n = 7). Group 1 was treated with vehicle sterile water (0.1 ml, i.m., 14 days); Group 2 received synbiotic (30 mg/kg, per os, 14 days); Group 3 was treated with ceftriaxone (300 mg/kg, i.m., 7 days); Group 4 was supplemented with ceftriaxone and synbiotic. Oxalate-degrading bacteria number and their total activity, urinary and plasma oxalate concentrations were measured on days 1 and 57 after the treatment withdrawal. The redoximetric titration with KMnO4 was adopted to evaluate the total oxalate-degrading activity in highly selective Oxalate Medium. Ceftriaxone treatment reduced total fecal oxalate-degrading activity independently on oxalate-degrading bacteria number and increased urinary and plasma oxalate concentrations. The synbiotic had higher oxalate-degrading activity vs probiotics and was able to restore fecal oxalate-degrading activity and significantly decrease urinary oxalate excretion in antibiotic-treated rats. Total fecal oxalate-degrading activity but not oxalate-degrading bacteria number should be thoroughly examined in the future to develop predictive diagnostics methods, targeted prevention and personalized treatment in kidney stone disease. Synbiotic supplementation had a beneficial effect on the total oxalate-degrading activity of gut microbiota, which resulted in decreased UOx excretion in rats.
... It is little wonder that antibiotics would affect gut microbiota and reduce the number of ODB [14,15]. The evidence of antibiotics' effect on ODB was generally based on quanti cation before and after antibacterial treatment [14,15]. ...
... It is little wonder that antibiotics would affect gut microbiota and reduce the number of ODB [14,15]. The evidence of antibiotics' effect on ODB was generally based on quanti cation before and after antibacterial treatment [14,15]. It has been demonstrated that the administration of different antibiotic classes reduces ODB in the gut for a long-time period after antibiotic exposure [14][15][16]. ...
... The evidence of antibiotics' effect on ODB was generally based on quanti cation before and after antibacterial treatment [14,15]. It has been demonstrated that the administration of different antibiotic classes reduces ODB in the gut for a long-time period after antibiotic exposure [14][15][16]. However, the effect of antibiotics on total ODA in fecal microbiota has never been evaluated before. ...
Background The present study aimed (i) to evaluate whether ceftriaxone treatment could affect not only intestinal oxalate-degrading bacteria number but their total activity to degrade oxalate and influence oxalate homeostasis in rats, (ii) to test the effect of commercially available probiotics and a synbiotic on total fecal oxalate-degrading activity, (iii) and to estimate the ability of synbiotic to restore fecal oxalate-degrading activity and ceftriaxone-induced disruption of oxalate homeostasis in rats.
Methods Twenty-eight female Wistar rats (200-300 g) were randomly divided into 4 groups (n = 7). Group 1 was treated with vehicle sterile water (0.1 ml, i.m., 14 days); Group 2 received synbiotic (30 mg/kg, per os, 14 days); Group 3 was treated with ceftriaxone (300 mg/kg, i.m., 7 days); Group 4 was supplemented with ceftriaxone and synbiotic. Oxalate-degrading bacteria number and their total activity, urinary and plasma oxalate concentrations were measured on days 1 and 57 after the treatment withdrawal.
Results Ceftriaxone treatment reduced total fecal oxalate-degrading activity independently on oxalate-degrading bacteria number and increased urinary and plasma oxalate concentrations. The synbiotic had a high oxalate-degrading activity vs probiotics and was able to restore fecal oxalate-degrading activity and significantly decrease urinary oxalate excretion in antibiotic-treated rats.
Conclusion Total fecal oxalate-degrading activity but not oxalate-degrading bacteria number should be thoroughly examined in the future to develop predictive diagnostics methods, targeted prevention and personalized treatment in kidney stone disease. Synbiotic supplementation had a beneficial effect on the total oxalate-degrading activity of gut microbiota, which resulted in decreased UOx excretion in rats.
... This condition is more common and less severe than PH1, facilitating clinical trials or nutritional research; the via of entry of oxalic acid in the body is by ingestion, similar to the postbiotics, which may increase efficacy and finally; there is a subset of health-conscious but ill-advised persons with hyperoxaluria causing kidney injury resulting from fashionable trends or diets (e.g., juicing) who would may also be prone to taking supplements such as O. formigenes postbiotics, especially if this would allow then to pursue their diets more safely. Another potential scenario of O. formigenes postbiotics use if prevention of antibiotic-associated urolithiasis, especially if long-term antibiotics are needed, as while on antibiotics, attempts at colonization by O. formigenes probiotics are expected to be futile [95]. Once on the market, post-registration studies will monitor the long-lasting safety and efficacy effects. ...
... formigenes postbiotics use if prevention of antibiotic-associated urolithiasis, especially if long-term antibiotics are needed, as while on antibiotics, attempts at colonization by O. formigenes probiotics are expected to be futile [95]. Once on the market, post-registration studies will monitor the long-lasting safety and efficacy effects. ...
Chronic kidney disease (CKD) is projected to become the fifth global cause of death by 2040 as a result of key shortcomings in the current methods available to diagnose and treat kidney diseases. In this regard, the novel holobiont concept, used to describe an individual host and its microbial community, may pave the way towards a better understanding of kidney disease pathogenesis and progression. Microbiota-modulating or -derived interventions include probiotics, prebiotics, synbiotics and postbiotics. As of 2019, the concept of postbiotics was updated by the International Scientific Association of Probiotics and Prebiotics (ISAPP) to refer to preparations of inanimate microorganisms and/or their components that confer a health benefit to the host. By explicitly excluding purified metabolites without a cellular biomass, any literature making use of such term is potentially rendered obsolete. We now review the revised concept of postbiotics concerning their potential clinical applications and research in kidney disease, by discussing in detail several formulations that are undergoing preclinical development such as GABA-salt for diet-induced hypertension and kidney injury, sonicated Lactobacillus paracasei in high fat diet-induced kidney injury, GABA-salt, lacto-GABA-salt and postbiotic-GABA-salt in acute kidney injury, and O. formigenes lysates for hyperoxaluria. Furthermore, we provide a roadmap for postbiotics research in kidney disease to expedite clinical translation.
... А это, в свою очередь, сказалось на повышенном уровне кальци-и оксалатурии с повышением риска развития МКБ [28]. Недавние исследования доказали, что существует более высокий риск развития нефролитиаза при применении антибиотиков, которые изменяют микробиом кишечника [29,30]. Подтверждения этому факту указаны в исследовании из Индии, где показано, что пациенты, принимавшие антибиотики, имеют меньшую заселенность кишечника O.formigenes и подвержены большей частоте развития МКБ [31]. ...
AIM: to analyse and synthesize Russian and foreign literature, to get acquainted with the concept of oxaluria, its types, transport mechanisms of oxalate transport in the intestine and the relationship between hyperoxaluria and inflammatory bowel diseases in order to identify possible options for therapeutic action on the mechanisms of development of these pathologies.
MATERIALS AND METHODS: the literature review was based on the Internet data, including bibliographic directories, books, journals, and original articles. The literature sources used for the article reflect the essence of the described problem to the fullest extent possible and can be useful for both practicing physicians and students of medical universities.
RESULTS: the gastrointestinal tract through epithelial transport of oxalate plays an exclusive role in oxalate homeostasis and hyperoxaluria. Metabolism of dietary oxalate and the formation of endogenous oxalate, its secretion, absorption, transport and biodegradation by intestinal microflora may influence the excretion of this compound by the kidneys. Knowledge of the interrelated relationships of the gut-kidney axis, mechanisms of transport, transport and biodegradation of oxalate, especially in inflammatory bowel disease, is of great importance for understanding the pathophysiology of hyperoxaluria as a risk factor for urinary stone formation with a point of pharmacological action in the gut. This literature review introduces the concept and forms of oxaluria, shows the classification of oxaluria, describes each form, and broadly explains the metabolism and mechanisms of oxalate transport in the human body. Special attention is given to intestinal hyperoxaluria and anion exchangers belonging to the large multifunctional SLC26 gene family, most of which are expressed throughout the gastrointestinal tract. The authors emphasise their current role in intestinal oxalate transport, as well as methods of possible drug action on the mechanisms of hyperoxaluria.
CONCLUSION: a multidisciplinary approach is needed to address the problems of intestinal hyperoxaluria and, consequently, the treatment of urolithiasis. The role of newly identified intestinal and renal anion exchangers is not fully understood, hence the targets and mechanisms of action on these types of exchangers with the possibility of preventing the development of urolithiasis are not fully understood. Further randomised studies on the problem under investigation are needed.
... Although the use of antibiotics has significantly reduced mortality in patients with urinary infectious stones, however, in recent years, antibiotic resistance has become increasingly severe, and even bacteria resistant to the last line of defense antibiotics have emerged, such as carbapenem-resistant Enterobacteriaceae and vancomycin-resistant Enterococcus [23]. Not only that, but a large number of studies have shown that the use of antibiotics perhaps aggravates the formation of urinary infectious stones [16,17,24,25], so understanding the bacterial flora and the genome of the flora in a patient's stones can help in the treatment of patients with infected stones. Use of antibiotics for more than 2 months in early and middle adulthood is associated with a higher risk of urinary stone disease in later life [26]. ...
Urinary infectious stones are challenging due to bacterial involvement, necessitating a comprehensive understanding of these conditions. Antibiotic-resistant urease-producing bacteria further complicate clinical management. In this study, analysis of urine and stone samples from urinary tract infection (UTI) patients revealed microbial shifts, gene enrichment in stones, and metabolic pathway disparities; antibiotic resistance gene trends were phylum-specific, urease-producing bacteria are at risk of acquiring AMR carried by Enterobacteriaceae under antibiotic, emphasizing potential AMR dissemination between them; Correlations of key pathogenic species in kidney stone and urine microbial communities highlight the need for targeted therapeutic strategies to manage complexities in UTIs; Stones and urine contain a variety of deleterious genes even before antibiotic use, and piperacillin/tazobactam better reduced the abundance of antibiotic resistance genes in stones and urine. The presence of diverse antibiotic resistance and virulence genes underscores challenges in clinical management and emphasizes the need for effective treatment strategies to mitigate risks associated with UTIs and urinary infectious stone formation. Ongoing research is vital for advancing knowledge and developing innovative approaches to address these urological conditions.
... In the case of incomplete resilience, it is logical to expect a reduction or even disappearance of certain functions performed by the missing bacteria, possibly the oxalotrophic bacteria, which could promote the development of calcium oxalate stones [59][60][61]. Studies in humans showed that oral antibiotic use was associated with an increased risk of kidney stones [62][63][64]. ...
Upper urinary tract urolithiasis is an emerging disease in cats, with 98% of kidney stones composed of calcium oxalate. In humans, disturbances in the intestinal and urinary microbiota are suspected to contribute to the formation of calcium oxalate stones. We hypothesized that similar mechanisms may be at play in cats. This study examines the intestinal and urinary microbiota of nine cats with kidney stones compared to nine healthy cats before, during, and after treatment with the antibiotic cefovecin, a cephalosporin. Initially, cats with kidney stones displayed a less diverse intestinal microbiota. Antibiotic treatment reduced microbiota diversity in both groups. The absence of specific intestinal bacteria could lead to a loss of the functions these bacteria perform, such as oxalate degradation, which may contribute to the formation of calcium oxalate stones. This study confirms the presence of a distinct urobiome in cats with kidney stones, characterized by greater richness and diversity compared to healthy cats. These findings highlight the potential of microbiota modulation as a strategy to prevent renal lithiasis in cats.
... The fragility of Oxalobacter formigenes poses a number of problems in the production and packaging processes, and the poor environment in the gastrointestinal tract means that only a small proportion of active Oxalobacter formigenes reaches the gastrointestinal tract, making colonization and oxalate degradation difficult to achieve [52]. At the same time, the use of antibiotics can also contribute to the loss of oxalate bacilli colonization in the body, which in turn is not effective in reducing oxalate in the long term for the prevention and treatment of calcium oxalate kidney stones [53,54]. Therefore, the use of less vulnerable probiotic bacteria carrying oxalate degrading systems into the gut to exert oxalate degrading capacity may be a good solution strategy. ...
Numerous studies have shown that intestinal and urinary tract flora are closely related to the formation of kidney stones. The removal of probiotics represented by lactic acid bacteria and the colonization of pathogenic bacteria can directly or indirectly promote the occurrence of kidney stones. However, currently existing natural probiotics have limitations. Synthetic biology is an emerging discipline in which cells or living organisms are genetically designed and modified to have biological functions that meet human needs, or even create new biological systems, and has now become a research hotspot in various fields. Using synthetic biology approaches of microbial engineering and biological redesign to enable probiotic bacteria to acquire new phenotypes or heterologous protein expression capabilities is an important part of synthetic biology research. Synthetic biology modification of microorganisms in the gut and urinary tract can effectively inhibit the development of kidney stones by a range of means, including direct degradation of metabolites that promote stone production or indirect regulation of flora homeostasis. This article reviews the research status of engineered microorganisms in the prevention and treatment of kidney stones, to provide a new and effective idea for the prevention and treatment of kidney stones.
... Chronic antibiotic therapy is thought to deplete intestinal Oxalobacter, leading to elevated levels of oxalate and consequently an increased risk for hyperoxaluria. Data from recent studies suggest an association between antibiotic use and nephrolithiasis 5,10 . ...
We present a case of a 69-year-old man who presented for routine check-up and was incidentally found to have kidney failure with an initially unrevealing history and bland urinary sediment. He was diagnosed with oxalate nephropathy in the setting of chronic turmeric supplementation and chronic antibiotic therapy with associated diarrhea. Our case provides several key insights into oxalate nephropathy. First, the diagnosis requires a high index of clinical suspicion. It is uncommonly suspected clinically unless there is an obvious clue in the history such as Roux-en-Y gastric bypass or ethylene glycol poisoning. Diagnosis can be confirmed by histopathologic findings and corroborated by serum levels of oxalate and 24-hour urinary excretion. Second, the diagnosis can often be missed by the pathologist because of the characteristics of the crystals unless the renal pathologist has made it a rule to examine routinely all H&E sections under polarized light. This must be done on H&E, as the other stains dissolve the crystals. Third, one oxalate crystal in a routine needle biopsy is considered pathologic and potentially contributing to the AKI or to the CKD in an important way. Fourth, secondary oxalosis can be largely mitigated or prevented in many cases, especially iatrogenic cases. This can come through the surgeon or the gastroenterologist providing proper instructions to patients on an oxalate-restricted diet or other specific dietary measures. Lastly, this case highlights the success that results from cooperation and communication between the pathologist and the treating physician.
Keywords:
Oxalate Nephropathy; Turmeric; Curcumin
... Acredita-se que a antibioticoterapia crônica deplete o Oxalobacter intestinal, levando a níveis elevados de oxalato e, consequentemente, a um risco aumentado de hiperoxalúria. Dados de estudos recentes sugerem uma associação entre o uso de antibióticos e a nefrolitíase 5,10 . ...
We present a case of a 69-year-old man who presented for routine check-up and was incidentally found to have kidney failure with an initially unrevealing history and bland urinary sediment. He was diagnosed with oxalate nephropathy in the setting of chronic turmeric supplementation and chronic antibiotic therapy with associated diarrhea. Our case provides several key insights into oxalate nephropathy. First, the diagnosis requires a high index of clinical suspicion. It is uncommonly suspected clinically unless there is an obvious clue in the history such as Roux-en-Y gastric bypass or ethylene glycol poisoning. Diagnosis can be confirmed by histopathologic findings and corroborated by serum levels of oxalate and 24-hour urinary excretion. Second, the diagnosis can often be missed by the pathologist because of the characteristics of the crystals unless the renal pathologist has made it a rule to examine routinely all H&E sections under polarized light. This must be done on H&E, as the other stains dissolve the crystals. Third, one oxalate crystal in a routine needle biopsy is considered pathologic and potentially contributing to the AKI or to the CKD in an important way. Fourth, secondary oxalosis can be largely mitigated or prevented in many cases, especially iatrogenic cases. This can come through the surgeon or the gastroenterologist providing proper instructions to patients on an oxalate-restricted diet or other specific dietary measures. Lastly, this case highlights the success that results from cooperation and communication between the pathologist and the treating physician.
Keywords:
Oxalate Nephropathy; Turmeric; Curcumin
... Use of antibiotics is a contributing factor in the development of urolithiasis. Sulfa drugs, cephalosporins, f luoroquinolones, nitrofurantoin/methenamine and broad-spectrum penicillins prospectively increase the risk of urolithiasis [8,9]. In the present case, urolithiasis was rarely induced by cefazolin sodium pentahydrate. ...
We report a rare case of urolithiasis induced by cefazolin sodium pentahydrate and review the relevant literature. A 12-year-old girl with right kidney injury was admitted to our hospital, a computed tomography scan revealed that no signs of disease in her left kidney but her right kidney was traumatized severely. After receiving cefazolin sodium pentahydrate, 2.0 g by intravenous infusion daily for 10 days, urolithiasis was found in the left urinary tract by computed tomography scan. Later, the patient complained of left back pain, nausea and vomiting, and a further computed tomography scan showed calculi persisted in the left urinary tract, and some of which had caused left hydronephrosis. A double-J catheter was placed in the left ureter, but no calculi were seen to drain with urine in the next 2 weeks, those calculi were removed by a flexible ureteroscope.
... Oral antibiotic use and antibiotic exposure at a young age have been associated with an increased risk for stone formation in humans (61)(62)(63) (68). The loss of oxalate-degrading bacteria, such as O. formigenes, following antibiotic use has been suggested to contribute to increased kidney stone risk due to augmented urinary oxalate excretion (65). ...
Oxalobacter formigenes, a unique anaerobic bacterium that relies solely on oxalate for growth, is a key oxalate-degrading bacterium in the mammalian intestinal tract. Degradation of oxalate in the gut by O. formigenes plays a critical role in preventing renal toxicity in animals that feed on oxalate-rich plants. The role of O. formigenes in reducing the risk of calcium oxalate kidney stone disease and oxalate nephropathy in humans is less clear, in part due to difficulties in culturing this organism, and the lack of studies which have utilized diets controlled in their content of oxalate. Herein, we review the literature on the 40th anniversary of the discovery of O. formigenes, with a focus on its biology, its role in gut oxalate metabolism and calcium oxalate kidney stone disease, and potential areas of future research. Results from ongoing clinical trials utilizing O. formigenes in healthy volunteers and in patients with Primary Hyperoxaluria Type 1 (PH1), a rare but severe form of calcium oxalate kidney stone disease, will also be discussed. Information has been consolidated on O. formigenes strains and best practices to culture this bacterium, which should serve as a good resource for researchers.
... Additionally, the impact of prior antibiotic use on the gut and urinary microbiome and its subsequent role in the development of kidney stones is being increasingly demonstrated. [15][16][17] In the era of greater antibiotic stewardship, clinicians must remain vigilant and adamant about prescribing antibiotics judiciously. ...
The management of small, non-obstructing renal stones in adults with recurrent lower urinary tract infections remains unclear. Whereas for larger or obstructing stones the decision to intervene becomes clearer, for stones smaller than 5 to 6 mm the decision to intervene requires consideration of multiple factors. This review describes these factors, including history, imaging, laboratory studies, as well as a comprehensive review of the literature. It remains of utmost importance that patients have additional possible etiologies appropriately evaluated and managed prior to intervention for their small renal stones.
... Vari Autori hanno dimostrato che la colonizzazione dell'apparato digerente da parte di Oxalobacter formigenes limita l'assorbimento intestinale di ossalato, mantiene basse le sue concentrazioni sierica e urinaria e previene pertanto la formazione di calcoli. [15,16]. L'uso di antibiotici promuove la calcolosi renale in quanto impedisce la crescita intestinale di Oxalobacter formigenes e di altri batteri capaci di metabolizzare l'ossalato [17]; ...
L'iter diagnostico per giungere ad un corretto management del paziente con nefrolitiasi costituisce un tema centrale dell'attività clinica del nefrologo. Negli ultimi anni i tassi di incidenza e prevalenza della nefrolitiasi hanno mantenuto un trend in continua crescita nel mondo, mostrando una stretta correlazione con altre patologie croniche quali diabete mellito, ipertensione arteriosa, obesità, sindrome metabolica e insufficienza renale. Le linee guida internazionali indicano la tomografia computerizzata come metodica di prima scelta per tutti i pazienti adulti con sintomatologia acuta sospetta per nefrolitiasi ostruttiva. La pielografia endovenosa è più utile nel follow-up dei pazienti con nefrolitiasi recidivante e composizione del calcolo già nota, mentre gli elevati costi e i lunghi tempi di acquisizione delle immagini limitano l'utilizzo routinario della risonanza magnetica. Le ultime innovazioni tecnologiche hanno permesso di ridurre sempre di più il dislivello tra ultrasonografia e tomografia computerizzata. Il corretto settaggio dell'apparecchio ecografico, il ricorso a nuovi parametri per la determinazione della dimensione del calcolo e l'uso appropriato del modulo color Doppler contribuiscono a migliorare la risoluzione dell'immagine e, quindi, l'accuratezza diagnostica dell'ultrasonografia. Obiettivo di questa review è stato riesaminare le ultime evidenze sui fattori di rischio e sulla fisiopatologia della nefrolitiasi e mettere a confronto le diverse tecniche di imaging nella gestione del paziente con calcolosi renale, ponendo l'accento sul ruolo dell'ultrasonografia e sulle strategie (sia attuali che in fase di studio) volte a migliorarne l'accuratezza diagnostica.
... It has been postulated that the nephrolithiasis-associated gut and urinary microbiota dysbiosis could depend on increased exposure to antibiotic therapies [53]. This hypothesis is supported by two large population-based epidemiologic studies, showing that lifetime exposure to antibiotics, and particularly long-course treatments occurring during the younger age, are associated with increased risk of developing kidney stone disease [54,55]. ...
Recent studies have shown that patients with kidney stone disease, and particularly calcium oxalate nephrolithiasis, exhibit dysbiosis in their fecal and urinary microbiota compared with controls. The alterations of microbiota go far beyond the simple presence and representation of Oxalobacter formigenes, a well-known symbiont exhibiting a marked capacity of degrading dietary oxalate and stimulating oxalate secretion by the gut mucosa. Thus, alterations of the intestinal microbiota may be involved in the pathophysiology of calcium kidney stones. However, the role of nutrition in this gut-kidney axis is still unknown, even if nutritional imbalances, such as poor hydration, high salt, and animal protein intake and reduced fruit and vegetable intake, are well-known risk factors for kidney stones. In this narrative review, we provide an overview of the gut-kidney axis in nephrolithiasis from a nutritional perspective, summarizing the evidence supporting the role of nutrition in the modulation of microbiota composition, and their relevance for the modulation of lithogenic risk.
Citation: Louta, A.; Kanellopoulou, A.; Alexopoulou Prounia, L.; Filippas, M.; Tsami, F.F.; Vlachodimitropoulos, A.; Vezakis, A.; Polydorou, A.; Georgopoulos, I.; Gkentzi, D.; et al. Ceftriaxone Administration Abstract: Lithiasis is a known side effect of ceftriaxone administration in children. Sex, age, weight, dosage, and duration of intake have been reported as risk factors for the formation of calcification or stones in the bile and urine excretory systems of children who received ceftriaxone. The purpose of this systematic review is to investigate the reported effects of ceftriaxone administration in pediatric patients who were admitted to a hospital due to infection, the likelihood of gallstones, nephroliths, or precipitations in both the biliary and urinary systems, as well as investigate the relationship with their mother's history during pregnancy. Original studies and literature reviews from the PubMed database were included in the study. No time limit related to research or publication was set for the articles. The results were evaluated, aiming to understand the outcomes and identify any predisposing factors relevant to this side effect. Of the 181 found articles, 33 were appropriate for inclusion in the systematic review. The administered dose of ceftriaxone presented variability. Symptoms, such as abdominal pain and vomiting, were associated with ceftriaxone-related lithiasis in many cases. It was noted that most of the results were the outcomes of retrospective observation and not of prospective randomized research. Definitively, more randomized control studies with long-term outcomes are needed to identify the exact association between ceftriaxone and lithiasis in children.
The gut microbiota (GM) is currently considered as a pathogenic factor in a number of diseases. It is known that some gastrointestinal diseases cause a high risk of developing urolithiasis. The study gives modern data demonstrating the influence of the GM, in particular Oxalobacter formigenes, on the formation of oxalate kidney stones. The relationship between the presence of inflammatory bowel diseases and the use of antimicrobial drugs with oxalate homeostasis was demonstrated, methods for correcting the GM in patients with urolithiasis, including the use of probiotics and diet therapy, were analyzed. The studies presented in the article demonstrate that the correction of the GM can be considered as a therapeutic goal and be an actual component of the complex treatment and metaphylaxis of nephrolithiasis.
Epithelial oxalate transport is fundamental to the role occupied by the gastrointestinal (GI) tract in oxalate homeostasis. The absorption of dietary oxalate, together with its secretion into the intestine, and degradation by the gut microbiota, can all influence the excretion of this nonfunctional terminal metabolite in the urine. Knowledge of the transport mechanisms is relevant to understanding the pathophysiology of hyperoxaluria, a risk factor in kidney stone formation, for which the intestine also offers a potential means of treatment. The following discussion presents an expansive review of intestinal oxalate transport. We begin with an overview of the fate of oxalate, focusing on the sources, rates, and locations of absorption and secretion along the GI tract. We then consider the mechanisms and pathways of transport across the epithelial barrier, discussing the transcellular, and paracellular components. There is an emphasis on the membrane-bound anion transporters, in particular, those belonging to the large multifunctional Slc26 gene family, many of which are expressed throughout the GI tract, and we summarize what is currently known about their participation in oxalate transport. In the final section, we examine the physiological stimuli proposed to be involved in regulating some of these pathways, encompassing intestinal adaptations in response to chronic kidney disease, metabolic acid-base disorders, obesity, and following gastric bypass surgery. There is also an update on research into the probiotic, Oxalobacter formigenes, and the basis of its unique interaction with the gut epithelium. © 2021 American Physiological Society. Compr Physiol 11:1-41, 2021.
Purpose:
Calcium oxalate(CaOx) stone formation is influenced by urinary oxalate excretion. Stone formers with elevated urinary oxalate are commonly prescribed a low-oxalate diet or oral supplementation with Vitamin B6 and magnesium to reduce urinary oxalate. This study aims to compare the effects of dietary modification versus supplementation versus a combination of both on urinary oxalate.
Materials and methods:
We enrolled patients with a documented history of CaOx stones and newly diagnosed idiopathic hyperoxaluria. Patients were randomized into three treatment groups: low oxalate diet(D), supplementation with 25mg vitamin B6 and 400mg magnesium oxide(S), or both low oxalate diet and B6/magnesium supplementation(DS). Baseline and 3-month post-intervention 24-hour urine tests were obtained. The primary endpoint was change in 24-hour urinary oxalate(Ox24) at 12-weeks. Secondary endpoints included changes in other 24-hour urine parameters, compliance rates, and adverse effect rates.
Results:
In total, 164 patients were recruited and 62, 47, and 55 were enrolled into the D, S, and DS groups, respectively. Of these, 99 patients completed the study (56.5% of the D, 72.3% of the S, and 54.6% of the DS groups, respectively). Significant differences were noted in median percent reduction in Ox24 values(-31.1% vs.-16.0% vs.-23.9%,p=0.007) in the D, S, and DS groups, respectively. Furthermore, the percentages of patients within each treatment arm who realized a decrease in Ox24 were also significantly different: D=91.4% vs. S=67.6% vs. DS=86.7%, p=0.027. No significant adverse events were observed in any of the study arms.
Conclusion:
Low oxalate diet is more effective than B6/magnesium supplementation at lowering urinary oxalate in idiopathic hyperoxaluric stone formers. Combination therapy did not produce greater reductions in urinary oxalate than either of the monotherapy arms suggesting it is of little clinical utility. Further study with long-term longitudinal follow-up is required to determine if these treatment strategies reduce recurrent stone events in this population.
In recent years, a growing body of evidence has emerged on the benefits of plant-based diets on the prevention and treatment of lifestyle diseases. In parallel, data now exist regarding the treatment of chronic kidney disease (CKD) and its most common complications with this dietary pattern. Improving the nutrient quality of patients by including a higher proportion of plant-based foods while reducing total - and animal protein - intake may reduce the need for - or complement - nephroprotective medications, improve kidney disease complications, and, perhaps, favorably affect disease progression and patient survival. In this In Practice article, we review the available evidence on plant-dominant fiber-rich diet as it relates to kidney disease prevention, CKD incidence and progression, metabolic acidosis, hyperphosphatemia, hypertension, uremic toxins, need for kidney replacement therapy including dialysis, patient satisfaction and quality of life, and mortality. Further, concerns of hyperkalemia and protein inadequacy, which are often associated with plant-based diets, are also reviewed in the context of available evidence. It is likely that the risks of both issues may not have been as significant as previously thought while the advantages are vast. In conclusion, the risk-to-benefit ratio of plant-based diets appear to be tilting in favor of its more prevalent use.
Enteric hyperoxaluria is a distinct entity that can occur as a result of a diverse set of gastrointestinal disorders that promote fat malabsorption. This, in turn, leads to excess absorption of dietary oxalate and increased urinary oxalate excretion. Hyperoxaluria increases the risk of kidney stones and, in more severe cases, CKD and even kidney failure. The prevalence of enteric hyperoxaluria has increased over recent decades, largely because of the increased use of malabsorptive bariatric surgical procedures for medically complicated obesity. This systematic review of enteric hyperoxaluria was completed as part of a Kidney Health Initiative-sponsored project to describe enteric hyperoxaluria pathophysiology, causes, outcomes, and therapies. Current therapeutic options are limited to correcting the underlying gastrointestinal disorder, intensive dietary modifications, and use of calcium salts to bind oxalate in the gut. Evidence for the effect of these treatments on clinically significant outcomes, including kidney stone events or CKD, is currently lacking. Thus, further research is needed to better define the precise factors that influence risk of adverse outcomes, the long-term efficacy of available treatment strategies, and to develop new therapeutic approaches.
Purpose of review:
Enteric hyperoxaluria is commonly observed in malabsorptive conditions including Roux en Y gastric bypass (RYGB) and inflammatory bowel diseases (IBD). Its incidence is increasing secondary to an increased prevalence of both disorders. In this review, we summarize the evidence linking the gut microbiota to the risk of enteric hyperoxaluria.
Recent findings:
In enteric hyperoxaluria, fat malabsorption leads to increased binding of calcium to free fatty acids resulting in more soluble oxalate in the intestinal lumen. Bile acids and free fatty acids in the lumen also cause increased gut permeability allowing more passive absorption of oxalate. In recent years, there is more interest in the role of the gut microbiota in modulating urinary oxalate excretion in enteric hyperoxaluria, stemming from our knowledge that microbiota in the intestines can degrade oxalate. Oxalobacter formigenes reduced urinary oxalate in animal models of RYGB. The contribution of other oxalate-degrading organisms and the microbiota community to the pathophysiology of enteric hyperoxaluria are also currently under investigation.
Summary:
Gut microbiota might play a role in modulating the risk of enteric hyperoxaluria through oxalate degradation and bile acid metabolism. O. formigenes is a promising therapeutic target in this population; however, further studies in humans are needed to test its effectiveness.
Urinary stone disease (USD) is a major health concern. There is a need for new treatment modalities. Recently, our group provided evidence for an association between the GMB composition and USD. The accessibility of the Gut Microbiome (GMB) makes it an attractive target for investigation and therefore, in these studies we have evaluated the extent to which the whole gut microbial community in fecal transplants can affect urinary stone risk parameters in an animal model. Fresh fecal pellets were collected from Zucker lean rats, homogenized in PBS (100 mg/mL), filtered through a 70 μm strainer and then orally gavaged into C57BL/6NTac germ‐free mice. Twenty‐four hours urine collections and GMB analysis were performed over time for 1 month. Kidney and gut tissue were harvested from transplanted mice for western blot analysis of expression levels of the Slc26a6 transporter involved in oxalate balance. Urinary calcium decreased after fecal transplant by 55% (P < 0.001). Urinary oxalate levels were on average 24% lower than baseline levels (P < 0.001). Clostridiaceae family was negatively correlated with urinary oxalate at 4 weeks after transplant (r = −0.83, P < 0.01). There was a 0.6 unit average increase in urinary pH from a baseline of 5.85 (SE ± 0.028) to 6.49 (SE ± 0.04) (P < 0.001) after transplant. There was a concomitant 29% increase in gastrointestinal alkali absorption (P < 0.001) 4‐weeks after fecal transplant. Slc26a6 expression increased by 90% in the cecum after transplant. Our results suggest that the gut microbiome may impact metabolism, alters urinary chemistry, and thereby may influence USD; the accessibility of the GMB can potentially be leveraged for therapeutic interventions. This paper represents a very early publication in this field of urology suggesting that the GMB can alter urinary stone parameters important for stone risk.
There has been increasing interest in the human anaerobic colonic bacterium Oxalobacter formigenes because of its ability to metabolize oxalate, and its potential contribution to protection from calcium oxalate kidney stones. Prior studies examining the prevalence of this organism have focused on subjects in developed countries and on adults. Now using O. formigenes-specific PCR, we have compared the prevalence of these organisms among subjects in two remote areas in which modern medical practices have hardly been present with a USA group of mothers and their infants for the first three years of life. Among the Amerindians of the Yanomami-Sanema and Yekwana ethnic groups in Venezuela and the Hadza in Tanzania, O. formigenes was detected in 60–80% of the adult subjects, higher than found in adults from USA in this and prior studies. In young children, the prevalence was much lower in USA than in either tribal village. These data extend our understanding of the epidemiology of O. formigenes carriage, and are consistent with the hypothesis that the rising incidence of kidney stones is associated with the progressive loss of O. formigenes colonization in populations that have been highly impacted by modern medical practices.
Background Although intestinal and urinary microbiome perturbations are associated with nephrolithiasis, whether antibiotics are a risk factor for this condition remains unknown.
Methods We determined the association between 12 classes of oral antibiotics and nephrolithiasis in a population-based, case–control study nested within 641 general practices providing electronic health record data for >13 million children and adults from 1994 to 2015 in the United Kingdom. We used incidence density sampling to match 25,981 patients with nephrolithiasis to 259,797 controls by age, sex, and practice at date of diagnosis (index date). Conditional logistic regression models were adjusted for the rate of health care encounters, comorbidities, urinary tract infections, and use of thiazide and loop diuretics, proton-pump inhibitors, and statins.
Results Exposure to any of five different antibiotic classes 3–12 months before index date was associated with nephrolithiasis. The adjusted odds ratio (95% confidence interval) was 2.33 (2.19 to 2.48) for sulfas, 1.88 (1.75 to 2.01) for cephalosporins, 1.67 (1.54 to 1.81) for fluoroquinolones, 1.70 (1.55 to 1.88) for nitrofurantoin/methenamine, and 1.27 (1.18 to 1.36) for broad-spectrum penicillins. In exploratory analyses, the magnitude of associations was greatest for exposure at younger ages ( P <0.001) and 3–6 months before index date ( P <0.001), with all but broad-spectrum penicillins remaining statistically significant 3–5 years from exposure.
Conclusions Oral antibiotics associated with increased odds of nephrolithiasis, with the greatest odds for recent exposure and exposure at younger age. These results have implications for disease pathogenesis and the rising incidence of nephrolithiasis, particularly among children.
Nephrolithiasis is a common urological disease with high prevalence and recurrence rates. Characterizing gut microbiome profiles of nephrolithiasis patients may provide valuable insights and potential biomarkers for the disease. Therefore, we explored the relation between gut microbiome and nephrolithiasis using 16S ribosomal RNA (rRNA) gene sequencing. 13 patients with multiple kidney stones and 13 matched healthy controls were recruited. A decreasing trend in number of observed species in nephrolithiasis patients was detected, although statistical significance was not reached (p = 0.086). The inter-group variability in community structure by beta diversity analysis showed a clear separation between nephrolithiasis patients and healthy controls. Twenty genera differentiated significantly in relative abundance between nephrolithiasis patients and healthy controls (all p < 0.05). Among the 20 genera, Phascolarctobacterium, Parasutterella, Ruminiclostridium_5, Erysipelatoclostridium, Fusicatenibacter and Dorea were correlated with the concentration of the trace elements in blood, including potassium, sodium, calcium and chlorinum. Characteristic microbiome in nephrolithiasis patients was also identified by linear discriminant analysis effect size (LEfSe). These findings may provide novel and non-invasive potential diagnostic biomarkers for nephrolithiasis, and contribute to prevention and treatment of nephrolithiasis from the perspective of maintaining micro-ecological equilibrium in gut.
Hyperoxaluria due to endogenously synthesized and exogenously ingested oxalates is a leading cause of recurrent oxalate stone formations. Even though, humans largely rely on gut microbiota for oxalate homeostasis, hyperoxaluria associated gut microbiota features remain largely unknown. Based on 16S rRNA gene amplicons, targeted metagenomic sequencing of formyl-CoA transferase (frc) gene and qPCR assay, we demonstrate a selective enrichment of Oxalate Metabolizing Bacterial Species (OMBS) in hyperoxaluria condition. Interestingly, higher than usual concentration of oxalate was found inhibitory to many gut microbes, including Oxalobacter formigenes, a well-characterized OMBS. In addition a concomitant enrichment of acid tolerant pathobionts in recurrent stone sufferers is observed. Further, specific enzymes participating in oxalate metabolism are found augmented in stone endures. Additionally, hyperoxaluria driven dysbiosis was found to be associated with oxalate content, stone episodes and colonization pattern of Oxalobacter formigenes. Thus, we rationalize the first in-depth surveillance of OMBS in the human gut and their association with hyperoxaluria. Our findings can be utilized in the treatment of hyperoxaluria associated recurrent stone episodes.
The trillions of microbes that colonize our adult intestine are referred to as the gut microbiome (GMB). Functionally it behaves as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. While the relationship between the GMB and kidney stone disease (KSD) has not been investigated, dysbiosis of the GMB has been associated with diabetes, obesity and cardiovascular disease. In this pilot study we sought to identify unique changes in the GMB of kidney stone patients compared to patients without KSD. With an IRB-approved protocol we enrolled 29 patients into our pilot study. 23 patients were kidney stone formers and six were non-stone forming controls. Specimens were collected after a 6h fast and were flash frozen in dry ice and then stored at -80 °C. Microbiome: determination of bacterial abundance was by analysis of 16 s rRNA marker gene sequences using next generation sequencing. Sequencing of the GMB identified 178 bacterial genera. The five most abundant enterotypes within each group made up to greater than 50 % of the bacterial abundance identified. Bacteroides was 3.4 times more abundant in the KSD group as compared to control (34.9 vs 10.2 %; p = 0.001). Prevotella was 2.8 times more abundant in the control group as compared to the KSD group (34.7 vs 12.3 %; p = 0.005). In a multivariate analysis including age, gender, BMI, and DM, kidney stone disease remained an increased risk for high prevalence for Bacteroides (OR = 3.26, p = 0.033), whereas there was an inverse association with Prevotella (OR = 0.37, p = 0.043). There were no statistically significant differences in bacterial abundance levels for Bacteroides or Prevotella when comparing patients with and without DM, obesity (BMI >30), HTN or HLD. 11 kidney stone patients completed 24 h urine analysis at the time of this writing. Looking at the bacterial genuses with at least 4 % abundance in the kidney stone group, Eubacterium was inversely correlated with oxalate levels (r = -0.60, p < 0.06) and Escherichia trended to an inverse correlation with citrate (r = -0.56, p < 0.08). We also compared bacterial abundance between uric acid (UA) stone formers (n = 5) and non UA stone formers (n = 18) and found no significant difference between them. We identified two genus of bacteria in the GMB that had significant association with KSD. Interestingly, components of the 24-h urine appear to be correlated to bacterial abundance. These preliminary studies for the first time associate differences in the GMB with kidney stone formation. Further studies are warranted to evaluate the potential causative role of preexisting dysbiosis in kidney stone disease.
Most studies of the human microbiome have focused on westernized people with life-style practices that decrease microbial survival and transmission, or on traditional societies that are currently in transition to westernization. We characterize the fecal, oral, and skin bacterial microbiome and resistome of members of an isolated Yanomami Amerindian village with no documented previous contact with Western people. These Yanomami harbor a microbiome with the highest diversity of bacteria and genetic functions ever reported in a human group. Despite their isolation, presumably for >11,000 years since their ancestors arrived in South America, and no known exposure to antibiotics, they harbor bacteria that carry functional antibiotic resistance (AR) genes, including those that confer resistance to synthetic antibiotics and are syntenic with mobilization elements. These results suggest that westernization significantly affects human microbiome diversity and that functional AR genes appear to be a feature of the human microbiome even in the absence of exposure to commercial antibiotics. AR genes are likely poised for mobilization and enrichment upon exposure to pharmacological levels of antibiotics. Our findings emphasize the need for extensive characterization of the function of the microbiome and resistome in remote nonwesternized populations before globalization of modern practices affects potentially beneficial bacteria harbored in the human body.
Oxalobacter formigenes (OF) may play a protective role in preventing calcium oxalate stones. This is the first prospective study to evaluate the effect of antibiotics on OF colonization. Intestinal colonization by OF is associated with reduced urinary oxalate excretion. Exposure to antibiotics may be an important factor determining rates of colonization.
The effect of antibiotics on OF colonization was compared in two groups: A group receiving antibiotics for gastric infection with Helicobacter pylori (HP) and a group without HP whose members were not receiving antibiotics. OF colonization in stool was detected by oxalate degradation at baseline and after 1 and 6 months.
The prevalence at baseline of intestinal colonization with OF was 43.1% among all patients screened. Among the 12 patients who were positive for OF who did not receive antibiotics, 11 (92%) had OF on stool tests at 1 month and 6 months. Of the 19 participants who were positive for OF and who received antibiotics for HP, only 7 (36.8%) continued to be colonized by OF on follow-up stool testing at 1 and 6 months (P=0.003 by Fisher exact test). Amoxicillin and clarithromycin caused 62.5% of subjects to become negative for OF at 1 month; 56.2% remained negative for OF at 6 months.
Antibiotics for HP infection effectively reduced colonization with OF, an effect present at 1 and 6 months after treatment. The lasting elimination of OF could be associated with hyperoxaluria and be a factor in recurrent kidney stone disease.
To elucidate the determinants of Oxalobacter formigenes colonization in humans.
O. formigenes is a gram-negative anaerobic bacterium that colonizes the colon of a substantial proportion of the normal population and metabolizes dietary and endogenous oxalate. The bacterium has been associated with a large reduction in the odds of recurrent calcium oxalate kidney stones. Subjects were 240 healthy individuals from Massachusetts and North Carolina. O. formigenes was detected by culture of fecal swabs. Information on factors of interest was obtained by telephone interviews and self-administered questionnaires.
The overall prevalence of O. formigenes was 38%. Use of specific antibiotics previously thought to affect the bacterium was significantly related to colonization, with prevalences of 17%, 27%, and 36%, for those who had used these drugs <1, 1-5, and >5 years ago, compared with 55% in nonusers. There were no significant associations with demographic factors, nutrient intake, or medical history, although the prevalence appeared to increase somewhat with increasing oxalate consumption.
Some antibiotics markedly affect colonization with O. formigenes. Although no other factor was identified as having a material influence on the prevalence of the bacterium, there is much to learn about how an individual acquires the organism and which factors affect persistence of colonization.
To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
Anaerobic bacteria that metabolize oxalic acid have only recently been isolated from the rumen and from other gastrointestinal habitats. They constitute a new genus and species, Oxalobacter formigenes. This report presents the first comparison of cultural counts of these organisms from human feces and indicates that numbers as high as 10(7)/g may be present in feces from normal humans. Rates of oxalate degradation by mixed bacterial populations in feces from seven normal humans ranged from 0.1 to 4.8 mumol/(g X h). With fecal samples from eight patients that had undergone jejunoileal bypass surgery, rates were much lower [0-0.006 mumol/(g X h)]. We propose that oxalic acid degradation by Oxalobacter formigenes may influence absorption of oxalate from the intestine and that lower rates or lack of oxalate degradation in the colons of jejunoileal bypass patients may contribute to the increased absorption of dietary oxalate and the hyperoxaluria commonly associated with such patients.
Oxalate degradation by the anaerobic bacterium Oxalobacter formigenes is important for human health, helping to prevent hyperoxaluria and disorders such as the development of kidney stones. Oxalate-degrading
activity cannot be detected in the gut flora of some individuals, possibly because Oxalobacter is susceptible to commonly used antimicrobials. Here, clarithromycin, doxycycline, and some other antibiotics inhibited oxalate
degradation by two human strains of O. formigenes. These strains varied in their response to gut environmental factors, including exposure to gastric acidity and bile salts.
O. formigenes strains established oxalate breakdown in fermentors which were preinoculated with fecal bacteria from individuals lacking
oxalate-degrading activity. Reducing the concentration of oxalate in the medium reduced the numbers of O. formigenes bacteria. Oxalate degradation was established and maintained at dilution rates comparable to colonic transit times in healthy
individuals. A single oral ingestion of O. formigenes by adult volunteers was, for the first time, shown to result in (i) reduced urinary oxalate excretion following administration
of an oxalate load, (ii) the recovery of oxalate-degrading activity in feces, and (iii) prolonged retention of colonization.
Microorganisms may have a role in the pathogenesis and prevention of kidney stones. The subjects of this review include nanobacteria, Oxalobacter formigenes, and lactic acid bacteria. Not reviewed here is the well-described role of infections of the urinary tract with Proteus species and other urease-producing organisms associated with struvite stone formation. Nanobacteria have been proposed to be very small (0.08-0.5 nm), ubiquitous organisms that could play a role in stone formation. The theory is that nanobacteria can nucleate carbonate apatite on their surfaces and thereby provide the nidus for stone formation. However, their existence remains uncertain and many investigators are openly skeptical. Recent investigations suggest that they are artifacts, and not actually living organisms, but their proponents continue to study them. O. formigenes is an obligate anaerobe which may be important in the prevention of stone formation. Its sole substrate for generation of ATP is oxalate. It may thereby metabolize its human host's dietary oxalate and diminish intestinal absorption and subsequent urinary excretion of oxalate. There is evidence that the organism's absence, perhaps sometimes due to courses of antibiotics, may be a cause of hyperoxaluria and stone formation. In early investigations, patients not colonized with the organism can be recolonized. Urinary oxalate can be diminished by accompanying an oxalate-containing meal with the organism. One study demonstrated that a preparation of lactic acid bacteria successfully reduced urinary oxalate excretion in 6 patients with calcium oxalate stones and hyperoxaluria. The mechanism of this effect is uncertain since these bacteria lacked the gene possessed by O. formigenes which codes for that organism's oxalate uptake mechanism. The author is currently completing a small randomized controlled clinical trial with this preparation in calcium stone-forming patients with idiopathic hyperoxaluria.
The primary goal of this study was to test the hypothesis that Oxalobacter colonization alters colonic oxalate transport thereby reducing urinary oxalate excretion. In addition, we examined the effects of intraluminal calcium on Oxalobacter colonization and tested the hypothesis that endogenously derived colonic oxalate could be degraded by lyophilized Oxalobacter enzymes targeted to this segment of the alimentary tract. Oxalate fluxes were measured across short-circuited, in vitro preparations of proximal and distal colon removed from Sprague-Dawley rats and placed in Ussing chambers. For these studies, rats were colonized with Oxalobacter either artificially or naturally, and urinary oxalate, creatinine and calcium excretions were determined. Colonized rats placed on various dietary treatment regimens were used to evaluate the impact of calcium on Oxalobacter colonization and whether exogenous or endogenous oxalate influenced colonization. Hyperoxaluric rats with some degree of renal insufficiency were also used to determine the effects of administering encapsulated Oxalobacter lysate on colonic oxalate transport and urinary oxalate excretion. We conclude that in addition to its intraluminal oxalate-degrading capacity, Oxalobacter interacts physiologically with colonic mucosa by inducing enteric oxalate secretion/excretion leading to reduced urinary excretion. Whether Oxalobacter, or products of Oxalobacter, can therapeutically reduce urinary oxalate excretion and influence stone disease warrants further investigation in long-term studies in various patient populations.
Oxalic acid is found in dietary sources (such as coffee, tea, and chocolate) or is produced by the intestinal microflora from
metabolic precursors, like ascorbic acid. In the human intestine, oxalate may combine with calcium, sodium, magnesium, or
potassium to form less soluble salts, which can cause pathological disorders such as hyperoxaluria, urolithiasis, and renal
failure in humans. In this study, an operon containing genes homologous to a formyl coenzyme A transferase gene (frc) and an oxalyl coenzyme A decarboxylase gene (oxc) was identified in the genome of the probiotic bacterium Lactobacillus acidophilus. Physiological analysis of a mutant harboring a deleted version of the frc gene confirmed that frc expression specifically improves survival in the presence of oxalic acid at pH 3.5 compared with the survival of the wild-type
strain. Moreover, the frc mutant was unable to degrade oxalate. These genes, which have not previously been described in lactobacilli, appear to be
responsible for oxalate degradation in this organism. Transcriptional analysis using cDNA microarrays and reverse transcription-quantitative
PCR revealed that mildly acidic conditions were a prerequisite for frc and oxc transcription. As a consequence, oxalate-dependent induction of these genes occurred only in cells first adapted to subinhibitory
concentrations of oxalate and then exposed to pH 5.5. Where genome information was available, other lactic acid bacteria were
screened for frc and oxc genes. With the exception of Lactobacillus gasseri and Bifidobacterium lactis, none of the other strains harbored genes for oxalate utilization.
Objectives
The involvement of the gut microbiota in the pathogenesis of calcium nephrolithiasis has been hypothesised since the discovery of the oxalate-degrading activity of Oxalobacter formigenes, but never comprehensively studied with metagenomics. The aim of this case–control study was to compare the faecal microbiota composition and functionality between recurrent idiopathic calcium stone formers (SFs) and controls.
Design
Faecal samples were collected from 52 SFs and 48 controls (mean age 48±11). The microbiota composition was analysed through 16S rRNA microbial profiling approach. Ten samples (five SFs, five controls) were also analysed with deep shotgun metagenomics sequencing, with focus on oxalate-degrading microbial metabolic pathways. Dietary habits, assessed through a food-frequency questionnaire, and 24-hour urinary excretion of prolithogenic and antilithogenic factors, including calcium and oxalate, were compared between SFs and controls, and considered as covariates in the comparison of microbiota profiles.
Results
SFs exhibited lower faecal microbial diversity than controls (Chao1 index 1460±363vs 1658±297, fully adjusted p=0.02 with stepwise backward regression analysis). At multivariate analyses, three taxa (Faecalibacterium, Enterobacter, Dorea) were significantly less represented in faecal samples of SFs. The Oxalobacter abundance was not different between groups. Faecal samples from SFs exhibited a significantly lower bacterial representation of genes involved in oxalate degradation, with inverse correlation with 24-hour oxalate excretion (r=−0.87, p=0.002). The oxalate-degrading genes were represented in several bacterial species, whose cumulative abundance was inversely correlated with oxaluria (r=−0.85, p=0.02).
Conclusions
Idiopathic calcium SFs exhibited altered gut microbiota composition and functionality that could contribute to nephrolithiasis physiopathology.
Hyperoxaluria is a major risk factor for kidney stones and has no specific therapy, although Oxalobacter formigenes colonization is associated with reduced stone risk. O. formigenes interacts with colonic epithelium and induces colonic oxalate secretion, thereby reducing urinary oxalate excretion, via an unknown secretagogue. The difficulties in sustaining O. formigenes colonization underscore the need to identify the derived factors inducing colonic oxalate secretion. We therefore evaluated the effects of O. formigenes culture conditioned medium (CM) on apical (14)C-oxalate uptake by human intestinal Caco-2-BBE cells. Compared with control medium, O. formigenes CM significantly stimulated oxalate uptake (>2.4-fold), whereas CM from Lactobacillus acidophilus did not. Treating the O. formigenes CM with heat or pepsin completely abolished this bioactivity, and selective ultrafiltration of the CM revealed that the O. formigenes-derived factors have molecular masses of 10-30 kDa. Treatment with the protein kinase A inhibitor H89 or the anion exchange inhibitor 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid completely blocked the CM-induced oxalate transport. Knockdown of the oxalate transporter SLC26A6 also significantly restricted the induction of oxalate transport by CM. In a mouse model of primary hyperoxaluria type 1, rectal administration of O. formigenes CM significantly reduced (>32.5%) urinary oxalate excretion and stimulated (>42%) distal colonic oxalate secretion. We conclude that O. formigenes-derived bioactive factors stimulate oxalate transport in intestinal cells through mechanisms including PKA activation. The reduction in urinary oxalate excretion in hyperoxaluric mice treated with O. formigenes CM reflects the in vivo retention of biologic activity and the therapeutic potential of these factors.
Oxalobacter formigenes, a member of the human colonic microbiota that plays a major role in net colonic oxalate transport and secretion, is protective against formation of calcium oxalate kidney stones. We now describe the prevalence, relative abundance and stability of O. formigenes in healthy young adults in the United States, as revealed by Human Microbiome Project (HMP) data from fecal samples from 242 healthy young adults who had 1-3 study visits. Samples underwent whole-genomic shotgun (WGS) sequencing, and/or 16S rRNA sequencing. Three datasets available from the processed sequence data were studied: WGS metagenomic analysis by alignment to reference genomes (HMSCP) or using MetaPhlAn, or QIIME analysis of the V1-3 or V3-5 16S sequences. O. formigenes was detected in fecal samples using both the WGS and 16S rRNA data. Analysis of the WGS dataset, using HMSCP, showed that 29 (31%) of 94 subjects were O. formigenes-positive while the V1-3 and V3-5 analyses were less sensitive for O. formigenes detection. When present, O. formigenes relative abundance varied over 3 log10, and was normally distributed. For 66 samples studied by all three methods, all assays agreed in 58 (88%). Of 14 subjects who were O. formigenes-positive at baseline, 13 (93%) were positive on follow-up visit, indicating the stability of colonization. O. formigenes appears to be stably present in fewer than half of healthy young USA adults and is most sensitively detected by WGS.
Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Background and objectives:
Kidney stones are heterogeneous but often grouped together. The potential effects of patient demographics and calendar month (season) on stone composition are not widely appreciated.
Design, setting, participants, & measurements:
The first stone submitted by patients for analysis to the Mayo Clinic Metals Laboratory during 2010 was studied (n=43,545). Stones were classified in the following order: any struvite, any cystine, any uric acid, any brushite, majority (≥50%) calcium oxalate, or majority (≥50%) hydroxyapatite.
Results:
Calcium oxalate (67%) was the most common followed by hydroxyapatite (16%), uric acid (8%), struvite (3%), brushite (0.9%), and cystine (0.35%). Men accounted for more stone submissions (58%) than women. However, women submitted more stones than men between the ages of 10-19 (63%) and 20-29 (62%) years. Women submitted the majority of hydroxyapatite (65%) and struvite (65%) stones, whereas men submitted the majority of calcium oxalate (64%) and uric acid (72%) stones (P<0.001). Although calcium oxalate stones were the most common type of stone overall, hydroxyapatite stones were the second most common before age 55 years, whereas uric acid stones were the second most common after age 55 years. More calcium oxalate and uric acid stones were submitted in the summer months (July and August; P<0.001), whereas the season did not influence other stone types.
Conclusions:
It is well known that calcium oxalate stones are the most common stone type. However, age and sex have a marked influence on the type of stone formed. The higher number of stones submitted by women compared with men between the ages of 10 and 29 years old and the change in composition among the elderly favoring uric acid have not been widely appreciated. These data also suggest increases in stone risk during the summer, although this is restricted to calcium oxalate and uric acid stones.
Hyperoxaluria significantly increases the risk of calcium oxalate kidney stone formation. Since several bacteria have been shown to metabolize oxalate in vitro, including probiotic bifidobacteria, we focused on the efficiency and possible mechanisms by which bifidobacteria can influence oxalate handling in vivo, especially in the intestines, and compared these results with the reported effects of Oxalobacter formigenes. Bifidobacterium animalis subsp. lactis DSM 10140 and B. adolescentis ATCC 15703 were administered to wild-type (WT) mice and to mice deficient in the hepatic enzyme alanine-glyoxylate aminotransferase (Agxt
−/−
, a mouse model of Primary Hyperoxaluria) that were fed an oxalate-supplemented diet. The administration of B. animalis subsp. lactis led to a significant decrease in urinary oxalate excretion in WT and Agxt
−/−
mice when compared to treatment with B. adolescentis. Detection of B. animalis subsp. lactis in feces revealed that 3 weeks after oral gavage with the bacteria 64 % of WT mice, but only 37 % of Agxt
−/−
mice were colonized. Examining intestinal oxalate fluxes showed there were no significant changes to net oxalate secretion in colonized animals and were therefore not associated with the changes in urinary oxalate excretion. These results indicate that colonization with B. animalis subsp. lactis decreased urinary oxalate excretion by degrading dietary oxalate thus limiting its absorption across the intestine but it did not promote enteric oxalate excretion as reported for O. formigenes. Preventive or therapeutic administration of B. animalis subsp. lactis appears to have some potential to beneficially influence dietary hyperoxaluria in mice.
Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP:
About 75% of urinary stones contain oxalate. As Oxalobacter formigenes is a Gram-negative anaerobic bacterium that degrades oxalate in the intestinal tract, we assessed the role of O. formigenes in oxalate metabolism by evaluating its intestinal absorption, plasma concentration, and urinary excretion. Of 37 calcium oxalate stone formers, 26 tested negative for O. formigenes and were compared with the 11 patients who tested positive. Patients provided 24-h urine samples on both a self-selected and a standardized diet. Urinary oxalate excretion did not differ significantly on the self-selected diet, but was significantly lower in O. formigenes-positive than in O. formigenes-negative patients under controlled, standardized conditions. Intestinal oxalate absorption, measured using [(13)C2]oxalate, was similar in the patients with or without O. formigenes. Plasma oxalate concentrations were significantly higher in noncolonized (5.79 μmol/l) than in colonized stone formers (1.70 μmol/l). Colonization with O. formigenes was significantly inversely associated with the number of stone episodes. Our findings suggest that O. formigenes lowers the intestinal concentration of oxalate available for absorption at constant rates, resulting in decreased urinary oxalate excretion. Thus, dietary factors have an important role in urinary oxalate excretion. The data indicate that O. formigenes colonization may reduce the risk of stone recurrence.Kidney International advance online publication, 27 March 2013; doi:10.1038/ki.2013.104.
To determine the sensitivity of 4 strains of Oxalobacter formigenes (Oxf) found in humans--HC1, Va3, CC13, and OxK--to varying concentrations of commonly prescribed antibiotics. Oxf gut colonization has been associated with a decreased risk of forming recurrent calcium oxalate kidney stones.
For each strain and each antibiotic concentration, 100 μL of an overnight culture and 100 μL of the appropriate antibiotic were added to a 7-mL vial of oxalate culture medium containing 20 mM oxalate. On the fourth day, vials were visually examined for growth, and a calcium oxalate precipitation test was performed to determine whether Oxf grew in the presence of the antibiotic.
All 4 Oxf strains were resistant to amoxicillin, amoxicillin/clavulanate, ceftriaxone, cephalexin, and vancomycin, and they were all sensitive to azithromycin, ciprofloxacin, clarithromycin, clindamycin, doxycycline, gentamicin, levofloxacin, metronidazole, and tetracycline. One strain, CC13, was resistant to nitrofurantoin, and the others were sensitive. Differences in minimum inhibitory concentration between strains were demonstrated.
Four human strains of Oxf are sensitive to a number of antibiotics commonly used in clinical practice; however, minimum inhibitory concentrations differ between strains.
The last nationally representative assessment of kidney stone prevalence in the United States occurred in 1994. After a 13-yr hiatus, the National Health and Nutrition Examination Survey (NHANES) reinitiated data collection regarding kidney stone history.
Describe the current prevalence of stone disease in the United States, and identify factors associated with a history of kidney stones.
A cross-sectional analysis of responses to the 2007-2010 NHANES (n=12 110). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Self-reported history of kidney stones. Percent prevalence was calculated and multivariable models were used to identify factors associated with a history of kidney stones.
The prevalence of kidney stones was 8.8% (95% confidence interval [CI], 8.1-9.5). Among men, the prevalence of stones was 10.6% (95% CI, 9.4-11.9), compared with 7.1% (95% CI, 6.4-7.8) among women. Kidney stones were more common among obese than normal-weight individuals (11.2% [95% CI, 10.0-12.3] compared with 6.1% [95% CI, 4.8-7.4], respectively; p<0.001). Black, non-Hispanic and Hispanic individuals were less likely to report a history of stone disease than were white, non-Hispanic individuals (black, non-Hispanic: odds ratio [OR]: 0.37 [95% CI, 0.28-0.49], p<0.001; Hispanic: OR: 0.60 [95% CI, 0.49-0.73], p<0.001). Obesity and diabetes were strongly associated with a history of kidney stones in multivariable models. The cross-sectional survey design limits causal inference regarding potential risk factors for kidney stones.
Kidney stones affect approximately 1 in 11 people in the United States. These data represent a marked increase in stone disease compared with the NHANES III cohort, particularly in black, non-Hispanic and Hispanic individuals. Diet and lifestyle factors likely play an important role in the changing epidemiology of kidney stones.
Background:Oxalobacter formigenes is a recently discovered anaerobic bacterium residing in the gastrointestinal tracts of most vertebrates, including humans. Evidence suggests that this bacterium plays an important symbiotic relationship with its hosts by regulating oxalic acid homeostasis. Oxalic acid is a ubiquitous toxic by-product of metabolism associated with numerous pathologic conditions, including hyperoxaluria, cardiac myopathy and conductance disorders, kidney stones, and even death. Despite the potential importance of O. formigenes in several major health disorders, the difficulty in culturing, isolating, and identifying this fastidious anaerobe has limited research of its disease associations. Because O. formigenes must use two unique enzymes to catabolize oxalic acid, this bacterium appeared to be a suitable model for DNA-based identification, thereby circumventing the labor-intensive procedures currently used.Methods and Results:In this study, genus- and group-specific oligonucleotide sequences were designed corresponding to homologous regions residing in the oxc gene that enodes for oxalyl-coenzyme A decarboxylase. A polymerase chain reaction (PCR)-based amplification of the 5′ end of this gene directly from genomic DNA isolated from various strains of O. formigenes was used to show that the genus- and group-specific oligonucleotide probes could identify and subgroup the bacterium. Field testing of this PCR-based detection system with 100 fecal cultures collected from children aged 0–12 years demonstrated the ease and efficacy with which O. formigenes can now be identified. Furthermore, these latter data provide a profile for the natural colonization of a human population with this intestinal bacterium.Conclusions:Development and use of this PCR-based detection system permit the rapid identification and classification of the gut-associated bacterium O. formigenes, thereby circumventing the need for the more labor-intensive and lengthy method currently used. The first field test of this detection system indicates that humans apparently do not become colonized with O. formigenes until they begin crawling about in the environment. Furthermore, studies investigating the association between several disorders (eg, kidney stones, irritable bowel syndrome, and hyperoxaluria) and the absence of the bacterium from the gut will now prove far easier.
Enteric colonization with Oxalobacter formigenes, a bacterium whose main energy source is oxalate, has been demonstrated to decrease the risk of recurrent calcium oxalate kidney stone formation. We assessed the impact of diets controlled in calcium and oxalate contents on urinary and fecal analytes in healthy subjects who were naturally colonized with O. formigenes or not colonized with O. formigenes.
A total of 11 O. formigenes colonized and 11 noncolonized subjects were administered diets controlled in calcium and oxalate contents. We assayed 24-hour urine collections and stool samples obtained on the last 4 days of each 1-week diet for stone risk parameters and O. formigenes levels. Mixed model analysis was used to determine the effects of colonization status on these variables.
Urinary calcium and oxalate excretion were significantly altered by the dietary changes in O. formigenes colonized and noncolonized individuals. Mixed model analysis showed significant interaction between colonization status and oxalate excretion on a low calcium (400 mg daily)/moderate oxalate (250 mg daily) diet (p = 0.026). Urinary oxalate excretion was 19.5% lower in O. formigenes colonized subjects than in noncolonized subjects on the low calcium/moderate oxalate diet (mean ± SE 34.9 ± 2.6 vs 43.6 ± 2.6 mg, p = 0.031).
Results suggest that O. formigenes colonization decreases oxalate excretion during periods of low calcium and moderate oxalate intake.
Humans lack the enzymes needed to metabolize endogenous and dietary oxalate, a toxic compound causing hyperoxaluria and calcium oxalate urolithiasis. Oxalate in humans can be eliminated through (1) excretion in urine, (2) forming insoluble calcium oxalate and elimination in feces, or (3) oxalate degradation by gastrointestinal (GIT) microorganisms. In this article, anaerobic oxalate catabolism in gut bacteria is reviewed, and the possible use of these bacteria as probiotics for treating kidney stone disease is evaluated. Oxalobacter formigenes and Lactobacillus and Bifidobacterium species are the best studied in this regard, with oxalate degradation in the lactic acid bacteria being both species- and strain-specific. The GIT oxalate-degrading bacteria express the catabolic enzymes formyl-CoA transferase (Frc) and oxalyl-CoA decarboxylase (Oxc). The genes encoding these proteins are clustered on the genomes and show strong phylogenetic relationships. Clinical trials investigating reduced hyperoxaluria through administering O. formigenes or its enzymes show a promising trend, but the data need confirmation through larger scale, well-controlled trials. Similar studies using Lactobacillus and Bifidobacterium species also show in vivo oxalate reduction, but these data are still controversial. In particular, further investigations need to determine whether there is a direct link between the lack of oxalate-degrading bacteria and hyperoxaluria and whether their absence is a risk factor. Key experiments linking microbial numbers, functional oxalate degradation, molecular analysis of the regulation of the genes involved, and the ability of the bacteria to survive in the gut are crucial elements in identifying suitable probiotics for treating kidney stone disease.
Patients with cystic fibrosis have an increased risk of hyperoxaluria, and of subsequent nephrocalcinosis and calcium-oxalate urolithiasis. Oxalate homoeostasis is controlled, in part, by the intestinal bacterium, Oxalobacter formigenes. The loss of this bacterium from the gut flora is associated with an increased risk of hyperoxaluria and calcium-oxalate urolithiasis. We investigated whether the absence of O. formigenes and the presence of hyperoxaluria are correlated in cystic fibrosis (CF) patients.
Stool specimens from 43 patients with CF aged 3-9 years and from 21 similarly aged healthy volunteers were examined for O. formigenes by culture and DNA analysis. At the same time, 24 h urine samples were collected and analysed for oxalate and other factors that promote or inhibit stone formation.
15 (71%) of 21 healthy volunteers but only seven (16%) of 43 CF patients were colonised with O. formigenes. Detection of O. formigenes in six of these seven patients required DNA-based identification, suggesting low numbers of colony-forming units, and the CF patient with normal numbers of O. formigenes was the only one of the 43 patients who had not been treated with antibiotics. All seven CF patients colonised with O. formigenes had normal urinary oxalate levels, but 19 (53%) of 36 patients not colonised with O. formigenes were hyperoxaluric, with the most severe hyperoxaluria occurring in young patients.
Absence of O. formigenes from the intestinal tract of CF patients appears to lead to increased absorption of oxalate, thereby increasing the risk of hyperoxaluria and its complications (eg, nephrocalcinosis, urolithiasis). Prolonged widespread use of antibiotics, and alterations of the gastrointestinal tract that occur in CF, may induce a permanent decolonisation in CF patients.
The present study was performed to detect the presence of an oxalate degrading bacteria Oxalobacter formigenes in the GI tract of calcium oxalate stone patients and normal individuals from North India. Furthermore, the possible relationship of this bacterium with number of stone episodes in this part of the world was also studied. The correlation of the presence or absence of O. formigenes with the urinary oxalate levels was evaluated.
DNA was extracted from the stool samples of 63 calcium oxalate stone formers and 40 normal individuals. Polymerase chain reaction (PCR) was performed using genus specific primers for O. formigenes. The presence of which was confirmed by Southern blotting. Urinary oxalate levels were tested in each patient.
As shown by PCR and Southern blotting, O. formigenes was present in 65% of normal individuals and in 30% of calcium oxalate stone formers. In patients with three or greater than three stone episodes colonies were present only in 5.6% of patients. Oxalate excretion was less in patients colonized with O. formigenes as compared to those with no colonization.
In North Indian population the absence of O. formigenes can lead to a significant increase in the risk of absorptive hyperoxaluria and resultant recurrent calcium oxalate stone episodes.
Oxalobacter formigenes is a member of the intestinal flora that degrades oxalate. This bacterium maintains an important symbiotic relation with its hosts by regulating oxalic acid absorption in the intestine as well as oxalic acid concentrations in plasma. We tried to define the prevalence of fecal O. formigenes positivity in healthy adults.
Whole-bacterial DNA was isolated directly from fresh stool samples obtained from 233 healthy adults known to be free of urolithiasis. Genus-specific oligonucleotide sequences corresponding to homologous regions residing in the oxc gene that encodes oxalyl-coenzyme A decarboxylase were designed. A PCR-based assay was done on the stool samples.
A PCR product of 416 bp encoding the oxc gene was detected in 197 of the 233 stool samples (76.8%). Adjusted to the Seoul population census 1995, the calibrated fecal O. formigenes-positive rate was estimated to be 76.7%: 79.2% in men and 74.2% in women, with no significance difference according to age or sex.
These results suggest that O. formigenes inhabits the intestine of three fourths of the normal Korean populations. These data provide a base for further studies to uncover the relation between O. formigenes and urolithiasis.
There is a growing body of evidence regarding the association between cystic fibrosis (CF) and nephrolithiasis and the role that Oxalobacter formigenes may have in that association.
We performed a MEDLINE search of "cystic fibrosis and nephrolithiasis" and "Oxalobacter formigenes." Epidemiological and experimental evidence and possible mechanisms explaining the association were critically reviewed.
Of patients with CF, 3.0% to 6.3% are affected with nephrolithiasis, a percentage greater than that of age-matched controls without CF, in whom the rate is 1% to 2%. Studies have suggested possible mechanisms for the association, including hyperuricosuria, hyperoxaluria, primary defects in calcium handling caused by mutation of the CF transmembrane regulator (CFTR), hypocitraturia, and lack of colonization with O formigenes, an enteric oxalate-degrading bacterium. The absence of colonization could be related to frequent courses of antibiotics.
Although the incidence of stones in patients with CF may be increased compared with controls without CF, many possible mechanisms are implicated. The relative contributions of these mechanisms remain uncertain. Future directions may include specific identification of lithogenic risks and therapy aimed at stone prevention in this population.
Larger body size may result in increased urinary excretion of calcium, oxalate, and uric acid, thereby increasing the risk for calcium-containing kidney stones. It is unclear if obesity increases the risk of stone formation, and it is not known if weight gain influences risk.
To determine if weight, weight gain, body mass index (BMI), and waist circumference are associated with kidney stone formation.
A prospective study of 3 large cohorts: the Health Professionals Follow-up Study (N = 45,988 men; age range at baseline, 40-75 years), the Nurses' Health Study I (N = 93,758 older women; age range at baseline, 34-59 years), and the Nurses' Health Study II (N = 101,877 younger women; age range at baseline, 27-44 years).
Incidence of symptomatic kidney stones.
We documented 4827 incident kidney stones over a combined 46 years of follow-up. After adjusting for age, dietary factors, fluid intake, and thiazide use, the relative risk (RR) for stone formation in men weighing more than 220 lb (100.0 kg) vs men less than 150 lb (68.2 kg) was 1.44 (95% confidence interval [CI], 1.11-1.86; P = .002 for trend). In older and younger women, RRs for these weight categories were 1.89 (95% CI, 1.52-2.36; P<.001 for trend) and 1.92 (95% CI, 1.59-2.31; P<.001 for trend), respectively. The RR in men who gained more than 35 lb (15.9 kg) since age 21 years vs men whose weight did not change was 1.39 (95% CI, 1.14-1.70; P = .001 for trend). Corresponding RRs for the same categories of weight gain since age 18 years in older and younger women were 1.70 (95% CI, 1.40-2.05; P<.001 for trend) and 1.82 (95% CI, 1.50-2.21; P<.001 for trend). Body mass index was associated with the risk of kidney stone formation: the RR for men with a BMI of 30 or greater vs those with a BMI of 21 to 22.9 was 1.33 (95% CI, 1.08-1.63; P<.001 for trend). Corresponding RRs for the same categories of BMI in older and younger women were 1.90 (95% CI, 1.61-2.25; P<.001 for trend) and 2.09 (95% CI, 1.77-2.48; P<.001 for trend). Waist circumference was also positively associated with risk in men (P = .002 for trend) and in older and younger women (P<.001 for trend for both).
Obesity and weight gain increase the risk of kidney stone formation. The magnitude of the increased risk may be greater in women than in men.
Oxalate is not only considered to be one of the main constituents of urinary stones, but it also has toxic effects on renal tubular epithelial cells, affecting the pathogenesis of nephrolithiasis. We tried to elucidate the effects of oxalate on human renal tubular epithelial cells (HK-2 cells). In addition, we investigated whether the toxic effect of oxalate occurs by apoptosis, and determined the expression of Bcl-2 family and caspase 9 proteins known as apoptosis-related protein. HK-2 cells were incubated with different concentrations of oxalate, and the effect of oxalate on the growth of the cells was assessed by MTT assay. A caspase-3 activity assay and TUNEL assay were performed on HK-2 cells after oxalate exposure in order to evaluate apoptosis. Immunoblot analysis of Bax, Bcl-2, Bcl-xL, and caspase-9 were performed. Oxalate exposure resulted in significant growth inhibition of HK-2 cells as oxalate concentrations increased. The toxic effect of oxalate on HK-2 cells was considered to occur through apoptosis, as suggested by the increase of caspase-3 activity. The percentage of positive nuclei stained using the TUNEL method was 18+/-2.3 in oxalate-treated cells and 2.5+/-0.9 in untreated cells (P<0.05). Bax and caspase-9 protein expression increased significantly as oxalate concentrations increased, but Bcl-2 protein expression decreased. There was no difference in Bcl-xL protein expression among the various concentrations of oxalate. Our results show that oxalate has a toxic effect on HK-2 cells and that this effect is induced by apoptosis, which may be mediated by an intrinsic pathway.
Most kidney stones are composed primarily of calcium oxalate. Oxalobacter formigenes is a Gram-negative, anaerobic bacterium that metabolizes oxalate in the intestinal tract and is present in a large proportion of the normal adult population. It was hypothesized that the absence of O. formigenes could lead to increased colonic absorption of oxalate, and the subsequent increase in urinary oxalate could favor the development of stones. To test this hypothesis, a case-control study involving 247 adult patients with recurrent calcium oxalate stones and 259 age-, gender-, and region-matched control subjects was performed. The prevalence of O. formigenes, determined by stool culture, was 17% among case patients and 38% among control subjects; on the basis of multivariate analysis controlling demographic factors, dietary oxalate, and antibiotic use, the odds ratio for colonization was 0.3 (95% confidence interval 0.2 to 0.5). The inverse association was consistently present within strata of age, gender, race/ethnicity, region, and antibiotic use. Among the subset of participants who completed a 24-h urine collection, the risk for kidney stones was directly proportional to urinary oxalate, but when urinary factors were included in the multivariable model, the odds ratio for O. formigenes remained 0.3 (95% confidence interval 0.1 to 0.7). Surprisingly, median urinary oxalate excretion did not differ with the presence or absence of O. formigenes colonization. In conclusion, these results suggest that colonization with O. formigenes is associated with a 70% reduction in the risk for being a recurrent calcium oxalate stone former.
- Chopra