Elevated fluid intake and the risk for pyelonephritis in urinary tract infection

IF 5.6 2区 医学 Q1 PHYSIOLOGY
Armin Just
{"title":"Elevated fluid intake and the risk for pyelonephritis in urinary tract infection","authors":"Armin Just","doi":"10.1111/apha.14216","DOIUrl":null,"url":null,"abstract":"<p>In the current issue of <i>Acta Physiologica</i>, Hamilton et al. investigate in a mouse model of urinary tract infection (UTI) the therapeutic value of elevated fluid intake for the risk of ascension to pyelonephritis, after cystitis has been established.<span><sup>1</sup></span> Urinary tract infection is considered the most common bacterial infection causing immense burden to affected patients and healthcare systems.<span><sup>2</sup></span> Women are more frequently affected than men. It is estimated that 50% of women will be affected at least once during their lifetime, and 30%–40% suffer from recurrent UTI. Costs are estimated to reach $2 billion per year in the USA.<span><sup>2</sup></span> Confinement to the lower urinary tract (cystitis) is considered a benign disease; however, the infection may ascend to the kidney (pyelonephritis) or in the worst case cause bacteremia and sepsis (urosepsis).<span><sup>2, 3</sup></span> The most effective therapy is antibiotic.<span><sup>4</sup></span> However, with regard to prevalence and further provocation of resistances, non-antibiotic treatment options are of growing importance.<span><sup>4</sup></span> Major non-antibiotic recommendations are cranberry products and elevated fluid intake.<span><sup>4</sup></span> While there is evidence and recommendation for increased fluid intake for prevention of recurrent UTI, it is unclear, whether this also helps to reduce the risk of ascension to pyelonephritis once cystitis is established. The latter question has been investigated by Hamilton et al.<span><sup>1</sup></span> The authors found that increasing fluid intake and thereby urine production, not only failed to reduce the risk for ascension but substantially augmented the occurrence and severity of pyelonephritis.</p><p>The urinary tract is not only open to the body surface, but the orifice anatomically close to the microbiotic reservoir of the gastrointestinal tract. Accordingly, UTI is a constant battlefield between bacteria and host, featuring a wide array of mechanisms on both the side of bacterial virulence and host defense.<span><sup>3, 5</sup></span> By far (80%) the most common pathogens causing UTI are uropathogenic <i>Escherichia coli</i> (UPEC).<span><sup>3, 5</sup></span> Most virulence factors of UPEC are genetically clustered in pathogenicity-associated islands<span><sup>3</sup></span> and include mechanisms for attachment to the urinary epithelium (adhesins), for survival and immune escape, as well as pathogenic toxins. The most important adhesins are fimbriae or pili,<span><sup>3, 5</sup></span> multimeric proteins assembled to form hair-like structures protruding from the outer membrane of the bacterium. Several types have been described (Type-1-, P-, FIC-, S-, curli-fimbria, and Dr-adhesin). Type-1-fimbria attach to mannose-rich polysaccharides on the surface of the urothelium, allowing attachment to and possibly invasion of the bladder wall and accordingly are important for cystitis. P-fimbria attach to galactose moieties on the renal epithelium and prevail in pyelonephritic UPECs.<span><sup>3, 5</sup></span> Survival in the harsh environment of urine is supported by the polysaccharide capsule, which also helps to resist immunologic attack and phagocytosis. The scarce iron is scavenged through siderophores such as aerobactin, which is secreted by the bacterium, chelates iron, and is subsequently reclaimed.<span><sup>3, 5</sup></span> Toxins include hemolysin, which can lyse erythrocytes and other cells,<span><sup>3, 5</sup></span> and cytotoxic necrotizing factor (CNF1), inducing stress fiber formation by disturbing intracellular rho-signalling. Host defense mechanisms include mechanical factors of outward-directed urine flow, valvular functions within the urinary tract, and the specialized multilayered urothelium with superficial uroplakin.<span><sup>3, 5</sup></span> Type A intercalated cells of the tubular epithelium are capable of phagocytosis, immune modulation, and secretion of small antimicrobial peptides (AMPs).<span><sup>6</sup></span> Antimicrobial peptides are small (5–20 kDa) cationic amphipathic peptides, which are bactericidal by disrupting bacterial cell membranes. Important members are RNAse7, alpha- and beta-defensins, catelicidins, and adrenomedullin.<span><sup>6</sup></span> Another line of defense is the secretion of uromodulin or Tamm–Horsfall protein.<span><sup>7</sup></span> This 100 kDa glycoprotein is secreted by tubular cells of the thick ascending limb and early proximal tubule.<span><sup>7</sup></span> Uromodulin serves several functions such as inhibition of kidney stone formation, stimulation of tubular reabsorption of sodium, calcium, and magnesium, immunomodulation, and systemic effects on oxidative stress and vascular calcification; however, the most intriguing function probably is in antibacterial defense of UTI.<span><sup>7</sup></span> Although uromodulin is not bactericidal, it can polymerize to a three-dimensional “fishing-net,” which may entangle urinary bacteria to facilitate their elimination by micturition. In addition, mannose moieties on uromodulin's glycoprotein structure may serve as “false” receptors for type-1-fimbriae of UPEC, thereby inhibiting their attachment to the urothelium.<span><sup>7</sup></span>\n </p><p>The study of Hamilton et al. builds on a mouse model of UTI developed and optimized by the group over several years.<span><sup>8</sup></span> UTI is induced by inoculation of a defined number of UPEC into the bladder of female mice. Animals then receive either ordinary chow or gel food for 24 h and pyelonephritis incidence and severity is determined in the kidneys. Separate animals showed that gel-feeding augmented urine production and diminished urine osmolarity substantially. Nonetheless, both incidence and severity of pyelonephritis were markedly enhanced in the gel-fed mice. Most severe infection was associated with urinary osmolalities of the same animals at 400–800 mosmol/kg. Compared to an average of ~1500 mosmol/kg of the chow-fed mice this urinary osmolality indicates substantial urinary dilution and hence major urine flow. Chow-fed animals with more concentrated urine had less severe or no pyelonephritis. Urinary uromodulin concentration was lower in gel-fed animals particularly in those with more severe pyelonephritis. Additional experiments on human urine samples revealed faster growth of EPEC in male than female urine, but lower levels of urinary uromodulin, at least when normalized to urine osmolality. This indicates that the higher incidence of cystitis in women is not caused by weak host defense, but thus presumably by closer vicinity to the gastrointestinal tract and shorter ascension pathway and occurs despite higher uromodulin levels and more adverse growth conditions in female urine. An interesting side finding is that average uromodulin concentrations were ~10-fold higher in mice than humans, which might be an adaptation to shorter ascension pathways and a putatively larger threat for UTI in mice.</p><p>Certainly, it is not clear at this stage, to what extent the findings in this mouse model are transferrable to humans, warranting further investigations. Nonetheless, the result of exaggerated instead of mitigated risk for ascending pyelonephritis resulting from elevated fluid intake in this preclinical setting is so astonishing, that it urges renewed evaluation of fluid therapy in UTI patients, particularly in the setting when cystitis is already established. Given the complexity of the interactions between virulence factors and defense mechanisms, the magnitude of fluid intake, gender, genetic factors, and the individual microbiome of UPECs may likely impact on the benefit or harm of fluid therapy in UTI.</p><p>The author declares no conflict of interest.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 9","pages":""},"PeriodicalIF":5.6000,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14216","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Physiologica","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/apha.14216","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

In the current issue of Acta Physiologica, Hamilton et al. investigate in a mouse model of urinary tract infection (UTI) the therapeutic value of elevated fluid intake for the risk of ascension to pyelonephritis, after cystitis has been established.1 Urinary tract infection is considered the most common bacterial infection causing immense burden to affected patients and healthcare systems.2 Women are more frequently affected than men. It is estimated that 50% of women will be affected at least once during their lifetime, and 30%–40% suffer from recurrent UTI. Costs are estimated to reach $2 billion per year in the USA.2 Confinement to the lower urinary tract (cystitis) is considered a benign disease; however, the infection may ascend to the kidney (pyelonephritis) or in the worst case cause bacteremia and sepsis (urosepsis).2, 3 The most effective therapy is antibiotic.4 However, with regard to prevalence and further provocation of resistances, non-antibiotic treatment options are of growing importance.4 Major non-antibiotic recommendations are cranberry products and elevated fluid intake.4 While there is evidence and recommendation for increased fluid intake for prevention of recurrent UTI, it is unclear, whether this also helps to reduce the risk of ascension to pyelonephritis once cystitis is established. The latter question has been investigated by Hamilton et al.1 The authors found that increasing fluid intake and thereby urine production, not only failed to reduce the risk for ascension but substantially augmented the occurrence and severity of pyelonephritis.

The urinary tract is not only open to the body surface, but the orifice anatomically close to the microbiotic reservoir of the gastrointestinal tract. Accordingly, UTI is a constant battlefield between bacteria and host, featuring a wide array of mechanisms on both the side of bacterial virulence and host defense.3, 5 By far (80%) the most common pathogens causing UTI are uropathogenic Escherichia coli (UPEC).3, 5 Most virulence factors of UPEC are genetically clustered in pathogenicity-associated islands3 and include mechanisms for attachment to the urinary epithelium (adhesins), for survival and immune escape, as well as pathogenic toxins. The most important adhesins are fimbriae or pili,3, 5 multimeric proteins assembled to form hair-like structures protruding from the outer membrane of the bacterium. Several types have been described (Type-1-, P-, FIC-, S-, curli-fimbria, and Dr-adhesin). Type-1-fimbria attach to mannose-rich polysaccharides on the surface of the urothelium, allowing attachment to and possibly invasion of the bladder wall and accordingly are important for cystitis. P-fimbria attach to galactose moieties on the renal epithelium and prevail in pyelonephritic UPECs.3, 5 Survival in the harsh environment of urine is supported by the polysaccharide capsule, which also helps to resist immunologic attack and phagocytosis. The scarce iron is scavenged through siderophores such as aerobactin, which is secreted by the bacterium, chelates iron, and is subsequently reclaimed.3, 5 Toxins include hemolysin, which can lyse erythrocytes and other cells,3, 5 and cytotoxic necrotizing factor (CNF1), inducing stress fiber formation by disturbing intracellular rho-signalling. Host defense mechanisms include mechanical factors of outward-directed urine flow, valvular functions within the urinary tract, and the specialized multilayered urothelium with superficial uroplakin.3, 5 Type A intercalated cells of the tubular epithelium are capable of phagocytosis, immune modulation, and secretion of small antimicrobial peptides (AMPs).6 Antimicrobial peptides are small (5–20 kDa) cationic amphipathic peptides, which are bactericidal by disrupting bacterial cell membranes. Important members are RNAse7, alpha- and beta-defensins, catelicidins, and adrenomedullin.6 Another line of defense is the secretion of uromodulin or Tamm–Horsfall protein.7 This 100 kDa glycoprotein is secreted by tubular cells of the thick ascending limb and early proximal tubule.7 Uromodulin serves several functions such as inhibition of kidney stone formation, stimulation of tubular reabsorption of sodium, calcium, and magnesium, immunomodulation, and systemic effects on oxidative stress and vascular calcification; however, the most intriguing function probably is in antibacterial defense of UTI.7 Although uromodulin is not bactericidal, it can polymerize to a three-dimensional “fishing-net,” which may entangle urinary bacteria to facilitate their elimination by micturition. In addition, mannose moieties on uromodulin's glycoprotein structure may serve as “false” receptors for type-1-fimbriae of UPEC, thereby inhibiting their attachment to the urothelium.7

The study of Hamilton et al. builds on a mouse model of UTI developed and optimized by the group over several years.8 UTI is induced by inoculation of a defined number of UPEC into the bladder of female mice. Animals then receive either ordinary chow or gel food for 24 h and pyelonephritis incidence and severity is determined in the kidneys. Separate animals showed that gel-feeding augmented urine production and diminished urine osmolarity substantially. Nonetheless, both incidence and severity of pyelonephritis were markedly enhanced in the gel-fed mice. Most severe infection was associated with urinary osmolalities of the same animals at 400–800 mosmol/kg. Compared to an average of ~1500 mosmol/kg of the chow-fed mice this urinary osmolality indicates substantial urinary dilution and hence major urine flow. Chow-fed animals with more concentrated urine had less severe or no pyelonephritis. Urinary uromodulin concentration was lower in gel-fed animals particularly in those with more severe pyelonephritis. Additional experiments on human urine samples revealed faster growth of EPEC in male than female urine, but lower levels of urinary uromodulin, at least when normalized to urine osmolality. This indicates that the higher incidence of cystitis in women is not caused by weak host defense, but thus presumably by closer vicinity to the gastrointestinal tract and shorter ascension pathway and occurs despite higher uromodulin levels and more adverse growth conditions in female urine. An interesting side finding is that average uromodulin concentrations were ~10-fold higher in mice than humans, which might be an adaptation to shorter ascension pathways and a putatively larger threat for UTI in mice.

Certainly, it is not clear at this stage, to what extent the findings in this mouse model are transferrable to humans, warranting further investigations. Nonetheless, the result of exaggerated instead of mitigated risk for ascending pyelonephritis resulting from elevated fluid intake in this preclinical setting is so astonishing, that it urges renewed evaluation of fluid therapy in UTI patients, particularly in the setting when cystitis is already established. Given the complexity of the interactions between virulence factors and defense mechanisms, the magnitude of fluid intake, gender, genetic factors, and the individual microbiome of UPECs may likely impact on the benefit or harm of fluid therapy in UTI.

The author declares no conflict of interest.

尿路感染时液体摄入量增加与肾盂肾炎的风险。
在本期《生理学报》(Acta Physiologica)上,汉密尔顿(Hamilton)等人在尿路感染(UTI)小鼠模型中研究了在膀胱炎确定后,增加液体摄入量对肾盂肾炎升高风险的治疗价值1。据估计,50% 的女性一生中至少会感染一次尿路感染,30%-40% 的女性会反复感染尿路感染。2 局限于下尿路(膀胱炎)被认为是一种良性疾病,但感染可能会上升到肾脏(肾盂肾炎),或在最严重的情况下引起菌血症和败血症(尿毒症)。4 虽然有证据并建议增加液体摄入量以预防复发性尿路感染,但目前还不清楚一旦膀胱炎确诊,这是否也有助于降低肾盂肾炎的风险。Hamilton 等人1 对后一个问题进行了研究。作者发现,增加液体摄入量从而增加尿量,不仅不能降低肾盂肾炎的风险,反而会大大增加肾盂肾炎的发生率和严重程度。因此,UTI 是细菌与宿主之间的持续战场,细菌的毒力和宿主的防御机制各不相同。3, 5 到目前为止(80%),导致 UTI 的最常见病原体是尿路致病性大肠杆菌(UPEC)。3, 5 尿路致病性大肠杆菌的大多数毒力因子在基因上聚集在致病性相关岛3 中,包括附着于尿路上皮(粘附素)、生存和免疫逃逸机制以及致病毒素。最重要的粘附素是缘膜或纤毛3、5 ,这是一种从细菌外膜伸出的多聚蛋白,可形成毛发状结构。目前已描述了几种类型(1 型粘附素、P 型粘附素、FIC 型粘附素、S 型粘附素、卷曲粘附素和 Dr 型粘附素)。1 型黏膜附着在尿道黏膜表面富含甘露糖的多糖上,可附着在膀胱壁上并可能侵入膀胱壁,因此对膀胱炎非常重要。P-纤膜附着在肾上皮的半乳糖分子上,在肾盂肾炎型 UPECs 中盛行。3, 5 在尿液的恶劣环境中存活需要多糖胶囊的支持,多糖胶囊还有助于抵抗免疫攻击和吞噬作用。3, 5 毒素包括溶血素(可溶解红细胞和其他细胞)3, 5 和细胞毒性坏死因子(CNF1),后者可通过干扰细胞内的 rho 信号诱导应激纤维的形成。宿主防御机制包括外向尿流的机械因素、尿路内的瓣膜功能以及具有表层尿路蛋白的特化多层尿路上皮、5 肾小管上皮的 A 型夹层细胞具有吞噬、免疫调节和分泌小型抗菌肽(AMPs)的能力。6 抗菌肽是小型(5-20 kDa)阳离子两性肽,通过破坏细菌细胞膜而具有杀菌作用。6 另一道防线是分泌尿囊素或 Tamm-Horsfall 蛋白。7 这种 100 kDa 的糖蛋白由粗升支和早期近端小管的肾小管细胞分泌。7 尿调节蛋白具有多种功能,如抑制肾结石的形成,刺激肾小管对钠、钙和镁的重吸收,免疫调节,以及对氧化应激和血管钙化的全身性影响;然而,最引人关注的功能可能是尿路感染的抗菌防御。7 汉密尔顿等人的研究建立在该研究小组历经数年开发和优化的 UTI 小鼠模型基础之上8 。 然后,动物接受普通饲料或凝胶食物 24 小时,并测定肾盂肾炎的发病率和严重程度。分离动物的结果表明,凝胶食物能显著增加尿量并降低尿液渗透压。然而,喂食凝胶的小鼠肾盂肾炎的发病率和严重程度都明显增加。最严重的感染与相同动物的尿渗透压为 400-800 mosmol/kg 有关。与饲料喂养小鼠平均约 1500 mosmol/kg 的尿渗透压相比,这一尿液渗透压表明尿液被大量稀释,从而导致尿量减少。周饲料喂养的小鼠尿液浓度较高,但肾盂肾炎较轻或没有肾盂肾炎。用凝胶饲料喂养的动物尿液中尿蛋白的浓度较低,尤其是肾盂肾炎较严重的动物。对人类尿液样本进行的其他实验表明,EPEC 在雄性尿液中的生长速度快于雌性尿液,但尿液中的尿液调节蛋白水平较低,至少在与尿液渗透压正常化时是如此。这表明,女性膀胱炎发病率较高的原因不是宿主防御能力较弱,而可能是由于女性尿液更靠近胃肠道,上升途径更短,尽管女性尿液中的尿液调节蛋白水平更高,生长条件更不利。一个有趣的侧面发现是,小鼠尿液中尿液调节蛋白的平均浓度比人类高 10 倍,这可能是为了适应小鼠较短的上升途径和较大的UTI威胁。然而,在这种临床前环境中,液体摄入量增加导致上升性肾盂肾炎的风险增加而不是减少的结果是如此惊人,这促使人们重新评估尿毒症患者的液体疗法,尤其是在膀胱炎已经形成的情况下。鉴于毒力因子和防御机制之间相互作用的复杂性,液体摄入量的大小、性别、遗传因素以及UPECs的个体微生物组可能会影响液体疗法在UTI中的利弊。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Acta Physiologica
Acta Physiologica 医学-生理学
CiteScore
11.80
自引率
15.90%
发文量
182
审稿时长
4-8 weeks
期刊介绍: Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.
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