Criteria for transplant recipients contemplating pregnancy
Chapter 1: "Permanent Maxillary and Mandibular Incisors"\n
Chapter 2: "The Permanent Maxillary and Mandibular Premolar Teeth"\n
Chapter 3: "Dental Anatomical Features and Caries: A Relationship to be Investigated"\n
Chapter 4: "Anatomy Applied to Block Anaesthesia"\n
Chapter 5: "Treatment Considerations for Missing Teeth"\n
Chapter 6: "Anatomical and Functional Restoration of the Compromised Occlusion: From Theory to Materials"\n
Chapter 7: "Evaluation of the Anatomy of the Lower First Premolar"\n
Chapter 8: "A Comparative Study of the Validity and Reproducibility of Mesiodistal Tooth Size and Dental Arch with the iTero Intraoral Scanner and the Traditional Method"\n
Chapter 9: "Identification of Lower Central Incisors"\n
The book is aimed toward dentists and can also be well used in education and research.',isbn:"978-1-78923-511-1",printIsbn:"978-1-78923-510-4",pdfIsbn:"978-1-83881-247-8",doi:"10.5772/65542",price:119,priceEur:129,priceUsd:155,slug:"dental-anatomy",numberOfPages:204,isOpenForSubmission:!1,isInWos:null,hash:"445cd419d97f339f2b6514c742e6b050",bookSignature:"Bağdagül Helvacioğlu Kivanç",publishedDate:"August 1st 2018",coverURL:"https://cdn.intechopen.com/books/images_new/5814.jpg",numberOfDownloads:7287,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfDimensionsCitations:3,hasAltmetrics:0,numberOfTotalCitations:4,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 4th 2016",dateEndSecondStepPublish:"October 25th 2016",dateEndThirdStepPublish:"July 16th 2017",dateEndFourthStepPublish:"August 16th 2017",dateEndFifthStepPublish:"October 16th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"178570",title:"Dr.",name:"Bağdagül",middleName:null,surname:"Helvacıoğlu Kıvanç",slug:"bagdagul-helvacioglu-kivanc",fullName:"Bağdagül Helvacıoğlu Kıvanç",profilePictureURL:"https://mts.intechopen.com/storage/users/178570/images/7646_n.jpg",biography:"Bağdagül Helvacıoğlu Kıvanç is a dentist, a teacher, a researcher and a scientist in the field of Endodontics. She was born in Zonguldak, Turkey, on February 14, 1974; she is married and has two children. She graduated in 1997 from the Ankara University, Faculty of Dentistry, Ankara, Turkey. She aquired her PhD in 2004 from the Gazi University, Faculty of Dentistry, Department of Endodontics, Ankara, Turkey, and she is still an associate professor at the same department. She has published numerous articles and a book chapter in the areas of Operative Dentistry, Esthetic Dentistry and Endodontics. 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Jeong",slug:"jin-su-jeong",email:"jsbliss@gmail.com",position:null,institution:null},{id:"223557",title:"Prof.",name:"Julio",middleName:null,surname:"Hernández-Blanco",fullName:"Julio Hernández-Blanco",slug:"julio-hernandez-blanco",email:"juliohb@unex.es",position:null,institution:null},{id:"223558",title:"Prof.",name:"Lorenzo",middleName:null,surname:"García-Moruno",fullName:"Lorenzo García-Moruno",slug:"lorenzo-garcia-moruno",email:"lgmoruno@unex.es",position:null,institution:null}]},book:{id:"6066",title:"Landscape Architecture",subtitle:"The Sense of Places, Models and Applications",fullTitle:"Landscape Architecture - The Sense of Places, Models and Applications",slug:"landscape-architecture-the-sense-of-places-models-and-applications",publishedDate:"September 19th 2018",bookSignature:"Amjad Almusaed",coverURL:"https://cdn.intechopen.com/books/images_new/6066.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"9738",leadTitle:null,title:"Non-Viral Vectors - Smart Materials for Gene Delivery Systems",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tAny mutation in the genome can cause a vast number of diseases, and the treatment of these diseases at the gene level is a very recently emerging approach in clinical practice with promising future implications. Gene therapy is described as the transfection of the therapeutic gene (DNA or RNA) either to the cytoplasm (RNA) or the nucleus (DNA) for curing various acquired and inherited diseases. This transfection can selectively improve or inhibit (antisense) gene function. As degradation of nucleic acids can occur during cellular uptake, which prevents the effective penetration of naked DNA or RNA into the cell, an appropriate carrier is needed.
\r\n\r\n\tThere are two main sorts of carriers which are called vectors: viral or non-viral vectors. Although viral vectors exhibit higher transfection efficiencies compared to non-viral based delivery, their adverse effects such as immunogenicity, oncogenicity, and cytotoxicity may cause limitations in clinical use. To overcome these drawbacks, non-viral vectors including, but not limited to polymers, lipids, and inorganic nanoparticles have recently drawn vast attention in gene therapy. This book aims to provide the reader with a comprehensive overview of the current state-of-the-art in non-viral vectors focusing on the potential employment of several nanomaterials which can be used in gene therapy.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"553c31658321b82e7166ffddc00ce5d8",bookSignature:"Associate Prof. Feray Bakan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9738.jpg",keywords:"Synthetic Polymer-Based Vectors, Chitosan, Polysaccharides, Peptides, Inorganic Nanoparticles, Magnetic Nanoparticles, Carbon-Based Nanomaterials, Lipid-Based Vectors, Cationic Liposomes, Lipid Nanoparticles, Lipoplexes, Genes",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 16th 2020",dateEndSecondStepPublish:"September 10th 2020",dateEndThirdStepPublish:"November 9th 2020",dateEndFourthStepPublish:"January 28th 2021",dateEndFifthStepPublish:"March 29th 2021",remainingDaysToSecondStep:"5 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr.Bakan conducted several national and international projects on biomedical nanomaterials and she has also participated in 3 international projects as a researcher. Dr. Bakan is a member of the Turkish Society for Microscopy and the Materials Research Society.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"210002",title:"Associate Prof.",name:"Feray",middleName:null,surname:"Bakan",slug:"feray-bakan",fullName:"Feray Bakan",profilePictureURL:"https://mts.intechopen.com/storage/users/210002/images/system/210002.png",biography:"Dr. Feray Bakan received her PhD degree in chemical engineering from Ataturk University, Turkey in 2011. She was awarded with post-doctoral fellowship from the Scientific and Technological Research Council of Turkey (TUBİTAK) and worked as a post-doctoral researcher at Department of Physics, Sabancı University, Turkey from 2011 to 2013. She is currently working as a research assistant professor at Sabancı University Nanotechnology Research and Application Center (SUNUM), Turkey. Her research interests focus on bioceramic nanomaterials’ synthesis and their health-related applications ranging from bone fracture healing to drug delivery systems. As a principal investigator, Dr. Bakan conducted several national and international projects on biomedical nanomaterials and she has also participated in 3 international projects as a researcher. Recently, she is working on calcium phosphate-based nanoparticles and cyclodextrin-drug inclusion complexes. Dr. Bakan has authored or co-authored 22 SCI/Scopus indexed papers, 6 international conference proceedings, and 1 book chapter published by IntechOpen. She has delivered numerous talks in national and international conferences and is a member of the Turkish Society for Microscopy and the Materials Research Society (MRS).",institutionString:"Sabancı University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Sabancı University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"17956",title:"Sexual and Reproductive Function in Chronic Kidney Disease and Effect of Kidney Transplantation",doi:"10.5772/16871",slug:"sexual-and-reproductive-function-in-chronic-kidney-disease-and-effect-of-kidney-transplantation",body:'\n\t\tChronic renal failure has been known to be associated with impotence and loss of libido in men and for many women, infertility and menstrual irregularities. There have been ongoing improvements in survival and quality of life after renal transplantation. These have been accompanied by an improvement in reproductive function and reversal of the relative infertility that occurs despite maintenance hemodialysis. One of the most impressive aspects of successful renal transplantation in the young person is the ability of the male patient to father a child and the female patient to give birth to a healthy baby.
\n\t\t\tPregnancy does not appear to have any adverse effect on the long-term survival of renal allografts. Because the outcome of pregnancy in transplantation are so different than those in chronic dialysis, it is advisable to treat end-stage renal disease patients with transplantation and wait until renal function has been stable before undertaking a planned pregnancy. Women are usually advised to wait at least 1 year after living-related kidney Transplantation, and 2 years after cadaveric kidney transplantation; however, waits of 5 years or more have been associated with impaired renal function post-partum.
\n\t\t\tAll women of child-bearing age should be counseled about the possibility and risks of pregnancy after kidney transplantation. Types of immunosuppressive regimens and assessment of graft function should be considered during preconception counseling. Contraceptive counseling should be provided before transplantation surgery, because ovulatory cycles may begin within 1 to 2 months after transplantation in women with grafts that are functioning well. It is strongly advised that every sexually active transplant recipient attend a family-planning counseling session, ideally before transplantation is performed. Breastfeeding is discouraged for patients taking any immunosuppressive drugs.
\n\t\t\tIn this chapter we will first have a short review on reproductive physiology in male and female and irregularities caused by end stage renal disease and then we will review the experience of women undergoing child birth after transplantation, with a focus on outcomes and suggested management strategies including contraception counseling.
\n\t\tThe male reproductive tract consists of the testis, epididymis, vas deference, prostate, seminal vesicles, ejaculatory duct, bulbouretral glands, and urethra. The testes contain two cell types: the Sertoli cells, which line the seminiferous tubules (the site of spermatogenesis), and the Leydig cells (the site of androgen synthesis). In the male, the pituitary gland secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which act on the testes. LH stimulates the synthesis and secretion of testosterone by the Leydig cells, and FSH stimulates the sertoli cells to secrete inhibin. FSH and testosterone act on the seminiferous tubules to stimulate spermatogenesis. In human it takes about 75 days for spermatogonia to develop into mature sperm cells (Berek 2002).
\n\t\t\t\tDuring ejaculation, mature spermatozoa are released from the vas deferens along with fluid from the prostate, seminal vesicle, and the bulbourethral glands. The semen released is a gelatinous mixture of spermatozoa and seminal plasma; however it thins out 20 -30 minutes after ejaculation by a process called liquefaction (Berek 2002).
\n\t\t\t\tBoth LH and FSH play roles in normal spermatogenesis. Thus, spermatogenesis does not occur spontaneously in men who have hypogonadotropic hypogonadism of prepubertal onset. Spermatogenesis can be initiated in these men by the administration of human chorionic gonadotropin (hCG), which has potent LH effects, and an FSH preparation, such as human menopausal gonadotropin (hMG) ( Finkel 1985).
\n\t\t\tFor many male patients with renal failure, impotence and loss of libido have been seen frequently; these problems may improve but rarely normalize with the institution of maintenance dialysis, commonly resulting in a decreased quality of life ( Holdsworth 1978; \n\t\t\t\t\t\tDiemont 2000\n\t\t\t\t\t; Rosas 2003). By comparison, a well-functioning renal transplant is much more likely to restore sexual activity; however, some features of reproductive function may remain impaired.
\n\t\t\t\tThe uremic milieu plays an important role in the genesis of sexual dysfunction in end stage renal disease. Psychologic and physical stresses that may contribute to disturbances in sexual function are also commonly present in patients with chronic renal failure ( Holdsworth 1978; Steele 1996; Toorians, Janssen et al. 1997).
\n\t\t\t\tAdvanced chronic kidney disease is associated with impaired spermatogenesis and testicular damage ( Holdsworth 1977; Holdsworth 1978). Semen analysis typically shows a decreased volume of ejaculate, oligo- or complete azoospermia, and a low percentage of motile sperm. Testicular histology shows reduced spermatogenic activity varying from decreased numbers of mature spermatocytes to complete aplasia of germinal elements. Other findings include damage to the seminiferous tubules, atrophy of Sertoli cells, and interstitial fibrosis and calcifications.
\n\t\t\t\t\tThe factors responsible for testicular damage in uremia are not well understood. It is possible that plasticizers in dialysis tubing, such as phthalate, may play a role in patients undergoing maintenance hemodialysis.
\n\t\t\t\t\tUremia also impairs gonadal steroidogenesis. The serum total and free testosterone concentrations are typically reduced, although the binding capacity and concentration of sex hormone-binding globulin are normal ( Lim 1976; Levitan 1984; de Vries 1984). Another manifestation of diminished testosterone secretory capacity is the subnormal and delayed testosterone response to the administration of human chorionic gonadotropin (HCG), a compound with luteinizing hormone-like actions (Stewart-Bentley 1974). By comparison, although the total plasma estrogen concentration is frequently elevated, the serum estradiol concentration is typically normal (Lim 1978).
\n\t\t\t\tThe serum concentration of luteinizing hormone (LH) is elevated in uremic men (Lim 1978); this is due to diminished testosterone feedback.
\n\t\t\t\t\tFollicle stimulating hormone (FSH) secretion is also elevated, although to a more variable degree ( Holdsworth 1978; de Vries 1984). Elevated FSH levels are probably the result of decreased testosterone and inhibin, a Sertoli cell product. The plasma FSH concentration tends to be highest in those uremic patients with the most severe damage to seminiferous tubules and presumably the lowest levels of inhibin. It has been suggested that increased FSH levels may portend a poor prognosis for recovery of spermatogenic function after renal transplantation. The gonadotropin reserve is generally intact, since the plasma level of both gonadotropins increased appropriately following administration of gonadotropin-releasing hormone (GnRH) (LeRoith 1980). The appropriate increase in FSH and LH in response to the administration of clomiphene (a nonsteroidal antiestrogen that stimulates gonadotropin secretion by blockade of estrogen mediated negative feedback on the hypothalamus) (Lim 1978), also indicates a normal gonadotropin reserve.
\n\t\t\t\tThe basal levels of serum prolactin are elevated in the majority of uremic patients, and the response to thyrotropin-releasing hormone (TRH) is reduced and delayed (Hagen C 1976). The mechanisms for the hyperprolactinemia in chronic renal failure are not well defined. Increased autonomous production rate of prolactin is a major mechanism for the hyperprolactinemia but decreased metabolic clearance rate may also play a role (Cowden 1981). The demonstration of resistance to stimulation or suppression of prolactin in CRF is consistent with increased autonomous production (Pece 1979). The state of secondary hyperparathyroidism of CRF may contribute to the increased production rate of prolactin, because PTH stimulates prolactin secretion (Issac 1978). The treatment of CRF patients with erythropoietin was associated with a decreased in serum prolactin levels and improvement in sexual dysfunction (Schaefer, Stanhope et al. 1989), but did not normalize rate of the response to TRH (Ramirez 1976). These observations suggest that either anemia and/or deficiency of erythropoietin per se participate in the genesis of the hyperprolactinemia of CRF.
\n\t\t\t\tVariable degrees of gynecomastia are often encountered in the male uremic patient treated with maintenance hemodialysis (Lim 1978). Gynecomastia usually develops during initial months of dialysis and regresses as dialysis continues. It may be transient or may last for periods of several months. The etiology may be related to the improvement in the nutritional status of uremic patient with dialysis theray and, as such, is similar to the mechanism of refeeding gynecomastia. It must be emphasized that in almost all cases of Gynecomastia, there is an alteration either in the ratio between the serum level of androgen and estrogen, in favor of the latter, or in the ratio between the action of androgen and estrogen at the tissue level ( Sawin 1973). Indeed, in patients with advanced CRF and those treated with hemodialysis, the ratio between the serum levels of free testosterone and estradiol is reduced because of a decreased in testosterone levels.
\n\t\t\t\tErectile dysfunction is defined as the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse. It may result from psychologic, neurologic, hormonal, arterial or cavernosal impairment or from a combination of these factors. Most of the studies in sexual dysfunctions in CRF patients have focused on impotence. Erectile dysfunction is common in patients with CRF and is observed in excess of 50% of these patients (Procci 1981). These data are based on results obtained from interviews with or by the completion of questionnaires by the patients and/or their spouses. Several factors appear to participate in the genesis of impotence in CRF patients. These include abnormalities in the neurohormonal control system of erection hormones of the hypothalamic-pituitary-gonadal axis, secondary hyperparathyroidism and, dysfunction of the corporal smooth muscle of the penis or in their response to relaxing stimuli and/or derangements in the arterial supply or the venous drainage of the penis (Schrier RW 2001). Patients with a history of abnormal erectile function prior to the onset of renal disease may have a secondary cause, such as a neuropathy or peripheral vascular disease.
\n\t\t\t\tThe presence of a neurogenic bladder suggests an underlying neuropathy, while findings of peripheral vascular disease point toward inadequate penile blood flow. The lack of secondary sexual characteristics combined with small soft testicles suggests hypogonadism. The ingestion of a number of medications, such as beta blockers and tricyclic antidepressants, may be a cause of erectile dysfunction.
\n\t\t\t\tAmong those without an obvious cause of impotence after an initial evaluation, consideration should be given to a psychologic difficulty, such as stress or depression. The values of Nocturnal Penile Tumescence (NPT) among a large population of uremic patients are significantly lower than normal. The administration of a nocturnal penile tumescence test may help distinguish between an organic and a psychologic disorder; the absence of an erection during sleep suggests underlying organic dysfunction. A positive test, however, does not exclude a physical cause.
\n\t\t\t\tThe first step in the treatment of uremic men with sexual dysfunction is increasing the delivered dose of dialysis, discontinuing medications with side effects of impotence and correcting the anemia of chronic renal disease. As an example, the administration of recombinant human erythropoietin to raise the hematocrit to 33 to 36 percent may enhance sexual function ( Delano 1989).
\n\t\t\t\t\tSildenafil has been effectively used in the treatment of erectile dysfunction in both hemodialysis and peritoneal dialysis patients and is often used for psychologic, vascular, or neurogenic causes ( Ifudu 1998; Palmer 1999; Turk 2001; Seibel 2002; Rosas 2003; Grossman 2004). Concurrent use of sildenafil and nitrates in any form, regularly or intermittently, is contraindicated.
\n\t\t\t\t\tSince the elevation of serum levels of prolactin plays a role in the impotence of male uremic patient, correction of hyperprolactinemia by bromocriptin is also associated with improvement of sexual dysfunction.
\n\t\t\t\t\tCabergoline, which causes nausea much less often than does bromocriptine and is at least as effective in treating hyperprolactinemia, should be tried first (Biller BM; Molitch ME; Vance ML; Cannistraro KB; Davis KR; Simons JA; Schoenfelder JR; Klibanski A 1996 ). The administration of testosterone to uremic men usually fails to restore libido or potency, despite normalized serum testosterone.
\n\t\t\t\t\tA vacuum tumescence device may be effective in restoring potency in uremic impotent males unresponsive to medical therapy. Administration of zinc is also a reasonable therapeutic option in uremic men.
\n\t\t\t\tKidney transplantation is the best and most effective option that can be offered to patients with severe renal damage to restore their health and the possibility of recovering their sexual and reproductive functions.
\n\t\t\t\tAfter successful transplantation, about two thirds of male patients observe improved libido and a return of sexual function to predialysis levels. Fertility as assessed by sperm counts, improves in half patients. The sex hormone profile tends to normalize; plasma testosterone and follicle stimulating hormone levels increase; and luteinizing hormone levels which may be high in dialysis patients, decrease to normal or low levels (Danovitch GM 2005).
\n\t\t\t\tThe factors that might cause certain difficulties for the recovery of sexual and reproductive functions in this type of patients include prolonged use of peritoneal dialysis, high follicle stimulating hormone (FSH) serum levels before the transplant, and a deficient function of the graft (De Celis and Pedron-Nuevo 1999).
\n\t\t\t\tA certain improvement has been reported as to semen quality in the three main parameters (number, morphology, and motility of the spermatozoa) in patients after kidney transplantation (De Celis and Pedron-Nuevo 1999).
\n\t\t\t\tSeveral studies conducted to evaluate the effects of immunosuppressive regimens suggest that some of these agents are potentially gonadotoxic since they affect testicular function and decrease fertility. This is mainly due to an indirect effect on the hypothalamus–pituitary–gonadal axis, or directly suppressant on the germinal epithelium of the testis, where the spermatogenetic process is primarily affected because of an interruption of the cycle needed for the development of an adequate amount of normal spermatozoa.
\n\t\t\t\tThis would result in oligo/asthenozoospermia, teratozoospermia, or azoospermia. Cyclosporine (CSA) is an important therapeutic agent and a common component in multiple immunosuppressive regimens used in recipients of kidney transplants and for a growing number of autoimmune disorders. Some studies imply that CSA is a potentially gonadotoxic drug, producing adverse effects on the reproductive capability in experimental models as well as in humans. In certain animal species, such as the Sprague–Dawley strain rats, Seethalakshmi et al. showed that the administration of CSA induces a deficient intratesticular synthesis of androgens and a reduction in spermatogenesis, although this reduction was reversible after exogenous gonadotrophins were administered (\n\t\t\t\t\t\tSeethalakshmi 1990\n\t\t\t\t\t). On the other hand, it has also been possible to observe the adverse effect of CSA by means of testicular biopsies performed in dogs (Seethalakshmi 1988) and rats (Seethalakshmi 1990) treated with CSA for short periods, where marked abnormalities in spermatogenesis were seen. Cyclosporine (CSA) may impair testosterone biosynthesis through direct damage to leydig cells and germinal cells, an indirect impairment of the hypothalamic-pituitary-gonadal axis has also been suggested.
\n\t\t\t\tComputer-aided sperm analysis (CASA) in infertile renal transplant recipients showed that both sperm concentration and straight line velocity (VSL) were inversely correlated to the cyclosporine whole blood trough levels. Stabilization of the cyclosporine whole blood trough level within the target therapeutic level could improve the fertility potential in kidney transplant recipients. Duration of hemodialysis before transplantation is also important in this regard. The time spent on hemodialysis is inversely correlated with the percentage of motile spermatozoa and the amplitude of lateral head displacement (ALH) (Eid, Abdel-Hamid et al. 1996).
\n\t\t\t\tAzathioprine (AZA), another drug that is frequently combined with CSA, is considered to be genotoxic (Olshan 1994). However, very few studies have analyzed the effects of AZA on the reproductive function of humans. Several studies suggest that prednisone might not be involved in sperm cell damage.
\n\t\t\t\tKaczmarek and coworkers found that heart transplant recipients treated with sirolimus had significantly lower free testosterone levels and significant higher levels of gonadotropic hormones luteinizing hormone and follicle-stimulating hormone compared with calcineurin inhibitor-based immunosuppression group (Kaczmarek 2004). Patients treated with sirolimus throughout the post-transplant period have a significantly reduced total sperm count compared to patients who did not receive sirolimus and a decreased proportion of motile spermatozoa. Moreover, the fathered pregnancy rate was lower in patients receiving sirolimus-based regimens (Zuber, Anglicheau et al. 2008).
\n\t\t\t\tThere is also concern about infertility associated with Ganciclovir which is used for treatment of cytomegalovirus (CMV) infection in transplant patients (Nevins and Dunn 1992). There is no increased incidence of neonatal malformations in pregnancies fathered by transplant recipients (Danovitch GM 2005).
\n\t\t\t\tRenal transplant recipients have all suffered from uremia. They have frequently spent a significant amount of time on dialysis and often have other comorbidities including hypertension and diabetes. Although a successful transplant may improve erectile function and return of libido, in many cases some degree of sexual dysfunction may persist. On the contrary a recent study showed that, erectile function worsens after RT in patients<45 yr (Mirone, Longo et al. 2009).
\n\t\t\t\t\tHypertension is common among transplant patients; CSA can exacerbate preexisting high blood pressure and also induce hypertension in patients, who had normal blood pressure prior to the kidney transplant.
\n\t\t\t\t\tAntihypertensive medications have negative effects on male sexual functions, such as libido and erection (Matthew RW 2005). Those medications which are implicated in erectile dysfunction include beta blockers (propranolol, labetalol), Alpha blockers (prazosin), sympatholytics (clonidine), vasodilators (hydralazine), and diuretics (thiazides, spironolactone).
\n\t\t\t\t\tOther drugs which may also play a role in erectile dysfunction in transplant patients are: HMG- CoA reductase inhibitors (lovastatin, simvastatin), antidepressant (serotonin reuptake inhibitors, tricyclics, monoamine oxidase inhibitors) and H2 antagonists (cimetidine, ranitidine, famotidine).
\n\t\t\t\t\tKetoconazole which is used in some transplant centers in order to increase cyclosporine level and reducing the cost of calcineurin inhibitors can cause erectile dysfunction because of its antiandrogenic action.
\n\t\t\t\t\tAdditional factors such as smoking and alcohol intake may account for failure of male sexual function to improve after transplantation.
\n\t\t\t\t\tCigarette smoking may induce vasoconstriction and penile venous leakage because of its contractile effect on the cavernous smooth muscle (Juenemann 1987). Alcohol in small amounts improves erection and increases libido because of its vasodilatory effect and the suppression of anxiety; however, large amounts can cause central sedation, decreased libido, and transient erectile dysfunction. Chronic alcoholism may cause hypogonadism and polyneuropathy, which may affect penile nerve function (Miller 1988).
\n\t\t\t\t\tAutonomic neuropathy may impair erectile function, and interruption of both hypogastric arteries may occasionally impair vascular supply.
\n\t\t\t\tMale patients should be asked about their sexual function and referred for urologic evaluation when necessary. Historically, androgens were touted as enhancing male sexual function. Today, more effective treatments are available, and testosterone therapy should be discouraged in men in whom erectile dysfunction is not associated with hypogonadism (Lue T F 2000). Sildenafil is a selective inhibitor of phosphodiesterase type 5, which inactivates cyclic GMP. Since its release in March 1998, it has become the drug of choice for most men with erectile dysfunction. When sexual stimulation releases nitric oxide into the penile smooth muscle, inhibition of phosphodiesterase type 5 by sildenafil causes a marked elevation of cyclic GMP concentrations in the glans penis, corpus cavernosum, and corpus spongiosum, resulting in increased smooth-muscle relaxation and better erection. Sildenafil has no effect on the penis in the absence of sexual stimulation, when the concentrations of nitric oxide and cyclic GMP are low (Lue T F 2000). Sildenafil has little effect on libido. Among more than 3700 men with 1631 patient years of exposure to sildenafil, most adverse events were mild to moderate and self-limited in duration (Esteban de la Rosa, Bravo Soto et al. 2003). Among men taking 25 to 100 mg of sildenafil, 16 percent reported headache, 10 percent flushing, 7 percent dyspepsia, 4 percent nasal congestion, and 3 percent abnormal vision (described as a mild and transient color tinge or increased sensitivity to light). These rates were twice as high among men taking 100 mg of sildenafil as among men who were taking lower doses. The visual effect is probably related to inhibition of phosphodiesterase type 6 in the retina. No chronic visual impairment has been reported, and the incidence of visual side effects was similar in diabetic and nondiabetic men (Price 1998). Nevertheless, because of the short duration of the clinical trials and the difficulty in detecting subtle retinal changes, the long-term safety of sildenafil treatment is still unknown. In men with retinal diseases, an ophthalmologic consultation may be warranted before sildenafil treatment is initiated. Adverse cardiovascular events (nasal congestion, headache, and flushing) were mild and transient in the majority of men. The rate of serious cardiovascular events (angina and coronary-artery disorder) is low. Sexual activity was thought to be a likely contributor to myocardial infarction in only 0.9 percent of 858 men in one study (Muller, Munder et al. 2009). Thus, the absolute increase in risk caused by sexual activity is low (one chance in a million for a healthy man). According to data from the National Center for Health Statistics and the Framingham Heart Study, the rate of death from myocardial infarction or stroke for men in the age range in which erectile dysfunction is common is approximately 170 per million men per week. Therefore, it appears that sildenafil therapy is safe for most men. Nevertheless, given that most of the men who died had underlying cardiovascular disease; cardiovascular status should be carefully assessed before treatment. The combination of nitrates and sildenafil has resulted in severe hypotension and 16 deaths in the United States. Therefore, nitrate therapy is an absolute contraindication to sildenafil therapy (Lue T F 2000).
\n\t\t\t\t\tSildenafil is absorbed well during fasting, and the plasma concentrations are maximal within 30 to 120 minutes (mean, 60). It is eliminated predominantly by hepatic metabolism, and the terminal half-life is about four hours. The recommended starting dose is 50 mg taken one hour before sexual activity. The maximal recommended frequency is once per day. On the basis of effectiveness and side effects, the dose may be increased to 100 mg or decreased to 25 mg (Lue T F 2000). There is no specific contraindication to use of sildenafil (Viagra) in transplant patients so long as standard precautions are taken regarding concomitant coronary artery disease.
\n\t\t\t\t\tOral vardenafil (Phosphodiesterase-5 Enzyme Inhibitor) therapy has a high efficacy and a low incidence of adverse events for kidney transplant recipients with ED (Yang, Ju et al. 2008). Vardenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE-5), which is responsible for degradation of cGMP in the corpus cavernosum; when sexual stimulation causes local release of NO, inhibition of PDE-5 by vardenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. so it can prolong erectile duration of ED patients (Wang and Huang 2009); at recommended doses, it has no effect in the absence of sexual stimulation.
\n\t\t\t\t\tTransurethral administration of alprostadil (synthetic form of prostaglandin E1) or intracavernous injection resulting in an erection sufficient for intercourse has been used successfully. The most effective intracavernous therapy used is a three-drug mixture containing papaverine, phentolamine, and alprostadil (trimix). The usual dose of trimix solution ranges from 0.1 to 0.5 ml. The rate of response to this solution is as high as 90 percent (Bennett 1991). In case of drug treatment failure, penile prosthesis can be considered even in transplanted patients (Lasaponara, Pasquale et al. 2009; Phe, Roupret et al. 2009).
\n\t\t\t\tThe menstrual cycle is a hormonally controlled process of events occurring through the hypothalamic-pituitary-ovarian axis and reflected by the histological changes in the endometrium.
\n\t\t\t\tThe normal menstrual cycle is a tightly coordinated cycle of stimulatory and inhibitory effects that results in the release of a single mature oocyte from a pool of hundreds of thousands of primordial oocytes.
\n\t\t\t\tThe menstrual cycle lasts 25 to 30 days in most women. It is divided into two successive phases: the follicular phase and the luteal phase. By convention, the day of menstruation is designated as day 1 of the menstrual cycle. The luteal phase is remarkably constant in length and lasts 13 to 15 days, but length of the follicular phase is variable. The average duration of flow is 4 to 6 days but can be as few as 2 days and as many as 7 days. A flow of longer than 7 days deserves evaluation (Higham 1990).The average blood loss during one menses is about 30 mL. A flow of 80 mL or more can lead to anemia and should be evaluated (Cohen and Galbraith 2001). However, it is not necessary to measure menstrual flow; a patient\'s perception of abnormal menses deserves evaluation and treatment.
\n\t\t\t\tBy definition menorrhagia is excessive and prolonged uterine bleeding at regular intervals; metrorrhagia is irregular, intermenstrual bleeding. Menometrorrhagia is heavy, prolonged, irregular bleeding at frequent, irregular intervals. Polymenorrhea is frequent, regular episodes of uterine bleeding at intervals of less than 21 days. Oligomenorrhea is irregular bleeding occurring at prolonged intervals of more than 35 days. Amenorrhea is absence of uterine bleeding (Sciarra J 2001).
\n\t\t\t\tThere is relatively little cycle variability among women between the ages of 20 and 40 years. In comparison, there is significantly more cycle variability for the first 5 to 7 years after menarche and for the last 10 years before cessation of menses (Treloar 1967).
\n\t\t\tMenstrual problem is common among women with renal insufficiency. It is partly because of abnormal bleeding time due to platelet dysfunction and also because of failure to ovulate or sustain adequate corpus luteum function.
\n\t\t\t\tAmenorrhea is common by the time the patient reaches end-stage renal disease. The menstrual cycle typically remains irregular with scanty flow after the initiation of maintenance dialysis, although normal menses are restored in some women( Holley 1997) In others, menorrhagia develops, sometimes leading to significant blood loss and increased transfusion requirements.
\n\t\t\t\tOligo/ anovulation is the major factor for these menstrual cycle abnormalities in uremic women. Uremia is associated with hypothalamic-pituitary-gonadal dysfunction.
\n\t\t\t\tLeptin is one of the responsible factors involving in this cycle abnormality. In general, serum leptin levels are significantly elevated in patients with renal failure, particularly when compared to age and body mass index (BMI)-matched controls ( Wolf 2002). Leptin appears to be one of several factors that influence the maturation of the gonadotropin-releasing hormone (GnRH) pulse generator.
\n\t\t\t\tHyperprolactinemia is common in women with chronic renal failure due to increased secretion and decreased metabolic clearance of this hormone ( Sievertsen 1980). The elevated prolactin levels may impair hypothalamic-pituitary function and contribute to sexual dysfunction and galactorrhea in these patients. Although kidney transplantation greatly improves menstrual pattern, but irregular bleeding is still a major problem among women with a transplanted kidney. In a study on 114 women with a transplanted kidney we found normal menstruation in 49%, oligo/ hypomenorrhea or amenorrhea in 31.3% and hypermenorrhea in 19.8% (\n\t\t\t\t\t\tLessan-Pezeshki, Ghazizadeh et al. 2004\n\t\t\t\t\t).
\n\t\t\t\tIn order to reduce the chance of endometrial hyperplasia that results from chronic stimulation of the endometrium with estradiol, medroxyprogesterone acetate (Provera), 10 mg/day orally for 5 days is prescribed. Patients with adequate endogenous estrogens will bleed within 3 to 5 days after medication, indicating adequate endogenous estrogen stimulation of the endometrium. Patients with relatively low levels of endogenous estrogens may have a limited response to the progesterone challenge.
\n\t\t\tSexual desire or drive is defined as the frequency or intensity with which a person desires to participate in sexual activity. Both organic and psychological variables contribute to this interest. Hormones can act on sexual behavior indirectly by influencing general mood. They can influence sexual interest levels by their peripheral action, such as by increasing genital vasocongestion and sexual sensation or by enhancing the sexual attractiveness of the female by means of smell. Women receiving chronic dialysis tend to experience decreased libido and reduced ability to reach orgasm.
\n\t\t\t\tUremic patient\'s sexual difficulties are often worsened by hemodialysis, with a lowered frequency of intercourse, reduced sexual desire, and an increased incidence of sexual failure (Thurm JA 1976 ). Initial treatment goals for uremic women with sexual dysfunction include increasing the adequacy of dialysis, and correcting the anemia of chronic renal failure.
\n\t\t\t\tAmenorrheic dialysis patients may have low estradiol levels; this may lead to vaginal atrophy and dryness, thereby resulting in discomfort during intercourse. Such patients may benefit from local estrogen therapy or vaginal lubricants. Successful transplantation is clearly the most effective means to restore normal sexual desire in women with chronic renal failure ( \n\t\t\t\t\t\tDiemont 2000\n\t\t\t\t\t). Sexual desire increases significantly after successful transplantation in most patients, however improvement in frequency of sexual activity and overall sexual satisfaction is not as high as sexual desire.
\n\t\t\t\tLow dose testosterone may be effective but, due to potential toxicity, is rarely used. The administration of bromocriptine may help restore sexual function in those with hyperprolactinemia.
\n\t\t\tFertility is reduced in the presence of end-stage renal disease. Conception is rare for women on dialysis, and occurs at a rate of one in every 200 patients (Rizzoni, Ehrich et al. 1992). Pregnancy is often diagnosed late because of menstrual irregularities; thus, early spontaneous abortion may be overlooked. The diagnosis of pregnancy may be difficult in women with end-stage renal disease; particularly because serum levels of beta-human chorionic gonadotropin (beta-hCG) may be increased in the absence of pregnancy. The main risks for a fetus include death, prematurity, and growth retardation. A review by Hou of 37 pregnancies associated with chronic renal dialysis found that 75% to 80% resulted in spontaneous abortion, stillbirth, or neonatal death. (Hou S 1987) Placental abnormalities included abruption, infarction, and microscopic areas of necrosis. No developmental abnormalities were reported, and the incidence of congenital abnormalities appeared to be no greater than for normal pregnancies.
\n\t\t\t\tHypertension is a major problem and may prove very difficult to control. Forty-nine percent of the patients reviewed by Hou became hypertensive during pregnancy. The infants of hepatitis carriers should receive hepatitis B immune globulin and vaccine in the first 72 hours to avoid becoming carriers.
\n\t\t\t\tSince 1976, chronic ambulatory peritoneal dialysis (CAPD) has been increasingly used to manage end-stage renal failure. It has several theoretical advantages over hemodialysis for the management of pregnant patients (Mahanty, Cherikh et al. 2001). A more constant intrauterine environment without rapid shifts in fluid, solutes, and electrolytes may benefit a fetus, Redrow compared eight pregnancies managed with peritoneal dialysis with seven managed with hemodialysis (Redrow 1988 ). Hypotensive episodes appear to be less frequent, hematocrits higher, and control of insulin and glucose levels more exact in the group on peritoneal dialysis. Further experience is needed to determine if this is the preferred mode of dialysis in pregnancy. If peritoneal dialysis is used, the exchange volumes should be decreased (eg, to 1.5 liters) and the frequency should be increased (Jungers and Chauveau 1997).
\n\t\t\t\tAn increased dose of dialysis appears to be beneficial, with reports of Kt/V values of 6 to 8, on hemodialysis 5-6 days per week (Henrich WL 2004), with the BUN being maintained at under 50 mg/dL or even under 45 mg/dL. Ameliorating the uremic milieu can avoid polyhydramnios, help control hypertension, and improve maternal nutrition. Increased doses of erythropoietin are required to maintain hemoglobin levels in an acceptable range (10 to 11 g/dl) and transfusions are sometimes required (Chao 2002). Protein intake should be 1 g/kg per day plus an additional 20 g/day for fetal growth. Diet should be supplemented with water soluble vitamins and zinc. Metabolic acidosis and hypocalcemia should be corrected. Careful uterine and fetal monitoring during hemodialysis, such as assessment of the fetal heart rate (particularly during the last portion of a session), combined with measures aimed at preventing dialysis-induced hypotension should be performed. In many cases, patients are hospitalized around week 20 of gestation for management of blood pressure, dialysis fluid balance, nutrition and anemia.
\n\t\t\t\t\tIf peritoneal dialysis is used, the exchange volumes should be decreased (eg, to 1.5 liters) and the frequency should be increased.
\n\t\t\t\tFertility is usually restored in women with renal transplants and pregnancy is common, occurring in 12% of women at childbearing age in one series (Sturgiss and Davison 1995). Pregnancy success rate exceeds 90% after the first trimester. The recovery of fertility is less common in women who undergo transplantation close to the end of their childbearing years (Hou S 1987). The first reported successful pregnancy occurred in a recipient of a kidney transplant from an identical twin sister performed in 1958 (Murray 1963). Since then, there have been hundreds of successful pregnancies reported in renal transplant recipients (Davison JM 1987). During the last decade there has been a steady increase in the number of pregnancies following renal transplantation (Sgro, Barozzino et al. 2002).
\n\t\t\t\tPregnancy in transplant recipients provides an opportunity to investigate biological processes that may have an impact on graft outcome as well as pregnancy outcome. For example, immunologic adjustments are believed to be involved in implantation as well as a successful acceptance of the allogenic fetus by their mother (Matthew RW 2005).
\n\t\t\t\tAlthough pregnancy can cause an increase in the glomerular filtration rate, which could theoretically lead to hyperfiltration and resultant glomerulosclerosis, the hyperfiltration of pregnancy is flow related, with no concomitant increase in intraglomerular pressure (Denton and Baylis 2007).
\n\t\t\t\t\tIn cyclosporine treated patients, graft dysfunction after pregnancy was seen in patients with higher mean serum creatinine levels and lower mean cyclosporine doses prior to conception (ArmentiVT, Radomski JS et al. 2000). Overall, in the majority of recipients studied, pregnancy does not appear to cause excessive or irreversible problems with graft function if the function of transplant organ is stable prior to pregnancy (Armenti, Constantinescu et al. 2008).
\n\t\t\t\t\tThe long-term effect of pregnancy on renal function is less clear. Two small studies in which matched nonpregnant controls were used found conflicting results: no deleterious effect in one with 15 year follow-up; and an increase in the plasma creatinine concentration of 0.5 to 0.7 mg/dL at 3 to 12 months in the other (Salmela, Kyllonen et al. 1993; Sturgiss and Davison 1995). The latter report also suggested that a second pregnancy might carry a greater risk, as renal function deteriorated in three of seven women (Salmela, Kyllonen et al. 1993).
\n\t\t\t\t\tThe incidence of acute rejection is not greater than expected for non-pregnant transplant patients. The incidence of acute rejection during pregnancy and three months after delivery varies between 9 and 14.5% in the published series. Rejection is sometimes difficult to diagnose and an ultrasound-guided biopsy may be helpful to diagnose acute pyelonephritis, recurrent glomerulonephritis, and severe pre-eclampsia. Renal biopsy should be performed before starting anti-rejection therapy, and high steroid doses are the first line of treatment. It has been suggested that acute rejection during the puerperium may be due to a return to a normal immune status or to a rebound effect from the altered gestational immune responsiveness. Therefore, immunosuppression should be re-adjusted immediately after delivery.
\n\t\t\t\tImmunosuppression in pregnancy is a concern from the perspective of both maternal and fetal safety issues. Blood volume and volume of distribution increase during pregnancy thus blood levels of immunosuppressive drugs are often lower, though there is no evidence that effective immunosuppression is inadequate if prepregnancy doses are used. We currently have limited information regarding the toxicities and teratogenic potentials of these agents, although our knowledge has recently increased as more women maintained on immunosuppressive therapy for solid organ transplants have opted to become pregnant.
\n\t\t\t\tThe most commonly used glucocorticoids are the short acting agents; prednisone, prednisolone and methyl prednisolone. Radiolabaled prednisone and prednisolone can cross the placenta, but maternal / cord blood ratios are approximately 10:1 (Beitins 1972). In utero exposure to high-dose steroid and immunosuppressive agents does not seem to be associated with an increased incidence of congenital anomalies in the offspring of pregnant women with a renal transplant. Adrenal insufficiency and thymic hypoplasia have occasionally been described in the infants of transplant recipients, but these problems are unlikely if the dose of prednisone has been decreased to 15 mg. Cases of cleft palate, mental retardation, have also been described in humans after in utero corticosteroid exposure. Glucocorticoid therapy during pregnancy can result in premature rupture of the membranes (PROM) and intrauterine growth restriction. The increased risk of PROM with prednisone therapy likely reflects the inhibitory effects of glucocorticoids on fetal membrane extracellular matrix synthesis. Alternatively, PROM may be the result of prednisone\'s stimulatory effects on fetal membrane, placental, and decidual corticotropin releasing hormone. Furthermore, pregnancy-induced hypertension, gestational diabetes, and osteoporosis can be exacerbated.
\n\t\t\t\t\tDoses of prednisone greater than 20 mg/d have been associated with serious maternal infection, however treatment of rejection with steroids, if necessary, should not be avoided during pregnancy (Lessan-Pezeshki M 2002).
\n\t\t\t\t\tCurrent data suggest that steroids and immunosuppressive agents in the doses used to prevent graft rejection in transplant recipients are well tolerated by the fetus. Long-term studies are required to determine whether there may be other effects, particularly an increase in the incidence of malignancies or abnormalities in the subsequent generation.
\n\t\t\t\t\tFDA rates the risk of prednisone use in pregnancy as C which implies that "Risks can not be ruled out".
\n\t\t\t\tAzathioprine is an antimetabolite, an imidazole derivative of 6- mercaptopurine. It is commonly used during pregnancy in transplant recipients. Radioactive labeling studies in humans have shown that 64 - 93 percent of azathioprine administered to mothers appears in fetal blood as inactive metabolites (Sarikoski 1973). Azathioprine can cause transient gaps or breaks in lymphocyte chromosomes. Germ cells and other tissues have not been studied. In the adult, azathioprine is metabolized to 6- mercaptopurine. The immature fetal liver lacks the enzyme inosinate pyrophosphorylase, needed for conversion, and the fetus is relatively protected from the effects of the drug (Lessan-Pezeshki M 2002). The desired drug dose of azathioprin is 2 mg/kg/day or less. In high doses (6 mg/kg), azathioprine is teratogenic in animals. In human studies low birth weights, prematurity, jaundice, respiratory distress syndrome and aspiration have been reported in kidney transplant recipients. Azathioprine has been associated with a dose related myelosuppression in the fetus, but leukopenia is not usually a problem in the neonate if the maternal white blood count is maintained at greater than 7500 /mm3 (Armenti, Constantinescu et al. 2008).
\n\t\t\t\t\tFDA rated azathioprine use during pregnancy as D which implies that "positive evidence of risk exists but potential benefit may outweigh the risk"
\n\t\t\t\tCyclosporine is a small cyclic polypeptide of fungal origin that inhibits calcineurin. There is little or no transplacental passage of cyclosporine in rodents (Safwenberg, Backman-Bave et al. 1977). In comparison, there are conflicting reports on the transfer of cyclosporine across the human placenta. Studies in pregnant rats have generally shown no effect of cyclosporine on organogenesis, although some renal proximal tubular cell damage can occur (Bailie, Elder et al. 2007). Human data showed that administration of cyclosporine was associated with low birth weights and a higher incidence of maternal diabetes, hypertension and renal allograft dysfunction. Cyclosporine metabolism appears to be increased during pregnancy and higher doses may be required to maintain plasma levels in the therapeutic range (Murirhead 1992). In women several years post-transplant with stable renal function, the pre-pregnancy dose can be continued. Some of the pregnancies in cyclosporine- treated women were complicated by preeclampsia. Cyclosporine increases production of thromboxane and endothelin, which have both been implicated in the pathogenesis of preeclampsia. Because of this, some physicians have suggested that the dose be limited to 2 to 4 mg/kg per day (Lindheimer Md and 1992).
\n\t\t\t\t\tAlthough the safety of cyclosporine is not well established in pregnancy, but it does not appear to be a major teratogen, as suggested by the results of a meta-analysis of 15 studies (Bar Oz 2001 ).
\n\t\t\t\t\tFDA rates the risk of cyclosporine use in pregnancy as C.
\n\t\t\t\tTacrolimus is another calcineurin inhibitor. Experience with tacrolimus in pregnancy is limited. Among 100 pregnancies in 84 women treated with tacrolimus, of whom 27 percent were renal transplant recipients, 68 progressed to a live birth, with 60 percent of deliveries being premature (Kaniz and 2000). It has been associated with neonatal hyperkalemia. As with cyclosporine, patients taking tacrolimus require frequent monitoring of renal function and drug levels. During pregnancy, the hepatic cytochrome p450 enzymes may be inhibited, which can lead to increased serum level of tacrolimus. The dose may therefore have to be significantly reduced to prevent toxicity (sometimes as much as 60 %) (Lessan-Pezeshki M 2002).
\n\t\t\t\t\tFDA rates the risk of tacrolimus use in pregnancy as C.
\n\t\t\t\tMMF is a selective antimetabolite which impairs lymphocyte function by blocking purine biosynthesis via inhibition of the enzyme inosine monophosphate dehydrogenase. Mycophenolate was developed as a replacement for azathioprine for maintenance immunosuppression. It is not nephrotoxic, and has less bone marrow toxicity than azathioprine.
\n\t\t\t\t\tMMF has been reported to cause head and eye malformations in the offspring of rat. Reported experience in human pregnancy with MMF is limited. There have been birth defects in few cases, but current data are insufficient to determine incidence of specific malformation. Among the 14 MMF-exposed offspring that has been reported, the underlying maternal conditions were kidney transplantation (N=7), lupus nephritis (N=4), liver transplantation, heart transplantation, and recurrent erythema multiforme. All were exposed in early pregnancy. The most distinctive malformation was moderate-to-severe microtia or anotia in 12, with external auditory canal atresia in 9. Other common craniofacial malformations and minor anomalies included orofacial clefts, hypertelorism, coloboma, and micrognathia. Six had cardiovascular malformations, of which three were either conotruncal or aortic arch defects (Anderka, Lin et al. 2009).
\n\t\t\t\t\tThe manufacturer of MMF recommends that women of child-bearing age should have a negative pregnancy test prior to the initiation of therapy. We currently recommend that allograft recipients who wish to conceive should change from MMF to azathioprine, if there are no contraindications to the switch. MMF should be stopped 6 weeks prior to conception.
\n\t\t\t\t\tFDA rates the risk of MMF use in pregnancy as D.
\n\t\t\t\tSirolimus is a macrolide antibiotic compound that is structurally related to tacrolimus. Following entry into the cytoplasm, sirolimus binds to the FK binding protein and presumably modulates the activity of the mammalian target of rapamycin (mTOR). The mTOR inhibits interleukin-2 mediated signal transduction, resulting in cell cycle arrest in the G1-S phase (Danovitch GM 2005). It causes delayed ossification in animal reproductive studies, and its use is contraindicated in human until more data are available. Its use should also be discontinued at least 6 weeks prior to attempted conception.
\n\t\t\t\t\tIn general, we recommend that women post-transplant who wish to conceive be switched prior to conception from sirolimus to cyclosporine. Upon delivery, it is recommended to switch the mother back to her basal immunosuppression in view of the potential benefits of the newer agents to prevent late acute rejection and chronic allograft nephropathy.
\n\t\t\t\t\tFDA rates the risk of sirolimus use in pregnancy as C.
\n\t\t\t\tOKT3 is a mouse antibody licensed for antirejection therapy, being directed against the CD3 antigen that is closely associated with the T cell receptor. It crosses the placenta. The National Transplantation Pregnancy Registry (NTPR) has reported the treatment of five women with OKT3 during pregnancy, with four surviving infants (Eisenberg 1997). The effect of polyclonal antibodies on the developing fetus is not known, but the IgG component would be expected to cross the placenta.
\n\t\t\t\tPooled human gamma-globulin preparations which were initially developed for the treatment of humoral immune deficiency disorders, proving to be invaluable in certain defined situations in clinical transplantation when used alone or in combination with plasmapheresis, such as antibody mediated rejection (Danovitch GM 2005). IgG is selectively transported across the placenta and the amount transferred increases with gestational age and dose. No cases of human deficiency virus (HIV) transmission have been reported with the use of IVIG, but adverse effects include thrombosis, alopecia, liver function disturbances, transient neutropenia, chills, nausea, flushing, tightness of chest and anaphylactic reaction in those with IgA antibodies.
\n\t\t\t\t\tThere is little information regarding the teratogenicity of IVIG in animals. One report showed that IVIG was well tolerated in pregnant mice with induced antiphospholipid antibody syndrome (Bakimer 1993). In humans, IVIG appears to cross the placenta after 32 weeks of gestation, even after modification that alters the Fc binding sites ( Hockel 1986). There have been no reports of fetal malformations in humans. However, IVIG is not completely benign, since hemolytic disease of the newborn and transmission of hepatitis C has been reported in selected cases.
\n\t\t\t\tLeflunomide is an antimetabolite with both immunosuppressive and antiviral activities. It has been used successfully in the treatment of polyoma virus nephropathy (Danovitch GM 2005). It has marked teratogenic properties.
\n\t\t\t\t\tFDA rates its use during pregnancy as X. This medication should not be used during pregnancy or breast feeding.
\n\t\t\t\tAll women of childbearing age should be counseled concerning the possibility and risks of pregnancy after kidney transplantation. Women who are not rubella immune should receive the rubella vaccine before transplantation, because live virus vaccines are contraindicated post transplantation (Hou S and 1999). Women are usually advised to wait at least one year after living related donor transplantation and two years after cadaveric renal transplantation (Lessan-Pezeshki M 2002). However, waiting 5 or more years may result in impaired renal function post partum that fails to recover, because of gradually deteriorating renal function secondary to chronic allograft nephropathy.
\n\t\t\t\tCriteria that should be ideally met before conception are shown in table 1.
\n\t\t\t\t\n\t\t\t\t\t\t\t\tAt least 1 year post transplantation\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tStable renal function with creatinine< 1.5 mg/dl\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tNo recent episodes of acute rejection\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tBP < 140/90 mmHg on medications\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tProteinuria <500 mg/ day\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tPrednisone < 15 mg/day\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tAzathioprine < 2 mg /kg/day\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tCyclosporine 2- 4 mg/ kg/ day\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\tNormal allograft ultrasound\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
Criteria for transplant recipients contemplating pregnancy
Preeclampsia is the most common complication, affecting 30% of pregnancies in renal transplant recipients, especially those with pre-transplant hypertension. Women with mild to moderate hypertension should be watched closely, warned about signs of early superimposed preeclampsia.
\n\t\t\t\t\tIn transplant recipients, changes in urinary protein excretion, plasma uric acid, platelet count, or liver function tests seem to be less useful as markers of preeclampsia than in the normal population. Blood pressure, renal function, proteinuria and weight should be monitored every 2-4 weeks, with more attention during the third trimester. Anti-hypertensive agents should be changed to those tolerated during pregnancy.
\n\t\t\t\tSafety and efficacy of Alpha Methyldopa are supported in several randomized trials and in 7.5 years follow up study of children born to treated mothers.
\n\t\t\t\t\tBeta Blockers; especially Atenolol and Metoprolol, appear to be safe and efficacious in late pregnancy; but fetal growth retardation has been noted when treatment was started in early or midgestation (Lindheimer MD.Davison JM 2001).
\n\t\t\t\t\tHydralazine is safe and used frequently as adjunctive therapy with α methyldopa and β blockers.
\n\t\t\t\t\tCalcium Channel Blockers such as Nifedipine, Nicardipine and Verapamile have been used in severe hypertension. They do not appear to be associated with any increase in congenital anomalies when used in the first trimester.
\n\t\t\t\t\tCalcium channel blockers may potentiate the hypotensive effects and neuromuscular blockade of magnesium and the interaction should be kept in mind when the drugs are used in women with a possibility of developing preeclampsia (Dynder 1988).
\n\t\t\t\t\tLabetalol appears to be as effective as methyldopa, but there is little follow up information on children born to mothers treated with this drug.
\n\t\t\t\t\tThe second and third trimester exposure to ACE inhibitors and AT1 antagonists may be associated with serious adverse fetal effects. Most of these problems have been disturbances of fetal and neonatal renal function, such as oligohydramnios, neonatal anuria, renal failure and death (Pryde 1993). The fetal outcome is generally good in women who present in early pregnancy while taking an ACE inhibitor if the drug is stopped.
\n\t\t\t\t\tContinued administration of an ACE inhibitor during pregnancy is contraindicated (Shotan 1994).
\n\t\t\t\t\tThe use of thiazide diuretics has been approved in women with chronic hypertension if prescribed before gestation; however, the recommendation is against their use in preeclamptic women, who often manifest decreased intravascular volumes and poor placental perfusion.
\n\t\t\t\tPregnancy is associated with suppression of the adaptive immune system. There is evidence that pregnant women in general are more susceptible to infection. Infection also is an important consideration in any patient receiving immunosuppressive drugs, including transplant patients.
\n\t\t\t\t\tUrinary tract infections are the most common bacterial infections and occur in up to 40% of pregnant transplant recipients, and are particularly common in patients who develop end-stage renal disease due to pyelonephritis. These women should have monthly screening urine cultures (Armenti, Constantinescu et al. 2008), if asymptomatic bacteriuria is present; the patient should be treated for 2 weeks and may be treated with suppressive doses of antibiotics for the rest of the pregnancy (Lessan-Pezeshki M 2002). If there is a need for invasive procedures such as fetal monitoring with scalp electrodes or intrauterine pressure monitoring, prophylactic antibiotics are recommended. Aseptic technique should be used for even minor surgery and steroid therapy augmented.
\n\t\t\t\t\tCytomegalovirus (CMV) remains the most frequent cause of viral infection post transplantation, however if the patient waits the recommended time after transplantation to become pregnant, she has passed the peak time of risk for CMV infection.
\n\t\t\t\t\t\tInfection in the fetus can be diagnosed by culturing the amniotic fluid. Titers of anti-CMV IgG and IgM during pregnancy are recommended, Ganciclovir has caused birth defects in animals when administered at twice human dose (Hou S and 1999). Herpes Simplex Virus (HSV) infection before 20 weeks gestation is associated with an increased rate of abortion. A positive HSV cervical culture at term is an indication for cesarean section. This can minimize the risk for neonatal herpes. Acyclovir can be safely used in pregnancy (Andrew 1992).
\n\t\t\t\t\t\tContinuous exposure to CsA in utero seems to impair T-, B- and NK-cell development and function in neonates. This effect is prolonged throughout the first year of life. In addition, low levels of serum immunoglobulins occur at the same time. This leads to suggest a delayed administration of classical vaccinations (after the first 6 months of life) in view of the potential risks of both sub-optimal immunologic responses, and adverse events after the administration of live, attenuated vaccines in infants born from young female organ transplant recipients (Schen 2002).
\n\t\t\t\t\t\tAn infant born to an HBSAg – positive mother should be given hepatitis B immunoglobulin within 12 hours of birth and HBV vaccine at another site within 48 hours followed by a booster injection at 1 and 6 month.
\n\t\t\t\t\t\tThe combination of immunoglobulin and vaccine offers protection for more than 90% of infants.
\n\t\t\t\t\t\tVertical transmission is believed to be low (<7%) with hepatitis C unless the patient is also infected with the human immunodeficiency virus (Lessan-Pezeshki M 2002).
\n\t\t\t\t\tThe incidence of pre-term delivery is 50%, because of presence of preeclampsia, renal function deterioration, fetal distress, premature rupture of membrane and premature labor. Intrauterine uterine growth retardation showing small-for-age babies is present in 20% of pregnancies. In general, successful fetal outcome is related to better renal function at conception. Despite immunosuppressive therapy there is no increase of fetal abnormalities.
\n\t\t\t\t\tA transplanted kidney rarely obstructs labor, vaginal delivery is recommended in most transplant recipient women. Cesarean section should be performed only for standard obstetric reasons. Delivery should occur in a specialized centre. Care must be taken to avoid fluid overload and infection. At the time of delivery, instrumentation should be minimized. Patients with renal insufficiency may be particularly at risk for water retention secondary to oxytocin (Lessan-Pezeshki M 2002).
\n\t\t\t\t\tIn the perinatal period, the steroid dose should be augmented to cover the stress of labor and to prevent postpartum rejection. Hydrocortisone, 100 mg every 6 hours, should be given during labor and delivery. In the puerperium, renal function, proteinuria, blood pressure, cyclosporine/tacrolimus blood levels and fluid balance should be closely monitored.
\n\t\t\t\tBreastfeeding is discouraged for patients taking any immunosuppressive drugs. Cyclosporine measurement in maternal blood and breast milk revealed a mean breast milk/ maternal blood level ratio of 84% (Munoz-Flores- thiagarajan and 2001).
\n\t\t\t\t\tAzathioprine is also appears in breast milk, these levels can be toxic to a newborn, and nursing is not recommended. Similar recommendations exist for tacrolimus or any other immunosuppressive agents.
\n\t\t\t\t\tIn summary, Because the outcome of pregnancy in transplantation are so different than those in chronic dialysis, it is advisable to treat end-stage renal disease patients with transplantation and wait until renal function has been stable for 1 to 2 years before undertaking a planned pregnancy. Such planned pregnancies offer the mother and fetus the best chance of favorable outcome. Before any woman with a renal transplant embarks on a pregnancy, she should be counseled by an obstetrician and transplant physician. Pregnancy appears to have no significant effect on graft function or survival; however, an important concern is that a mother may not survive to bring up the child that she bears. (Davison JM 1987)
\n\t\t\t\tMost female transplant recipients are unaware that transplantation has reversed the relative infertility associated with end-stage renal disease. The incidence of unwanted pregnancy among female kidney transplant recipients is significantly higher than general population. An unplanned pregnancy puts this special group at higher risk; either an induced abortion or continuing the pregnancy without a preconceptional evaluation could be harmful (\n\t\t\t\t\t\tLessan-Pezeshki and 2004\n\t\t\t\t\t). Outcomes for unwanted pregnancies are inferior to outcomes for planned pregnancies, so it is strongly advised that every sexually active transplant recipient attend a family-planning counseling session. Contraceptive counseling should be provided before transplantation surgery, because ovulatory cycles may begin within 1 to 2 months after transplantation in women with grafts that are functioning well. Women who do not desire pregnancy should be protected by an effective method of contraception. Surgical contraception (sterilization) should be considered for those who have completed their family. Tubal ligation can be performed at the time of transplantation surgery. Vasectomy is also an effective form of permanent contraception with little morbidity. The risk for infection may be increased with the use of an intrauterine device in immuno-compromised patients, and their efficacy decrease because of anti-inflammatory effects of immunosuppressive agents (Zerner J, Doil KL et al. 1981). New devices containing levonorgestrel are more effective than previous copper containing devices, with fewer side effects (Fong and Singh 1999).
\n\t\t\t\tDepot medroxyprogesterone acetate injection at three months interval is another effective method of contraception for these patients but return of fertility after discontinuation is not fast and loss of bone mineral density is a concern with its long-term use.
\n\t\t\t\tAlthough low dose estrogen progesterone oral contraceptive preparations are not contraindicated for transplant patients, but they should be used with caution because they may cause or aggravate hypertension or precipitate thromboembolism, especially in the context of cyclosporine immunosuppression. Calcineurin inhibitors levels should also be monitored soon after the contraceptive is started. Because of unfounded fear of using contraceptive pills, a significant number of kidney transplant recipients use less effective methods such as coitus interruptus. In our study on unwanted pregnancy we found that 92% of women with unwanted pregnancies were using coitus interruptus as the only method of contraception (Ghazizadeh 2005). Progestin-only pill is an option for women who have contraindication to use estrogen but their failure rate is higher than combined oral contraceptive pills. Barrier contraceptives such as male condom are the safest modality but depend on user compliance for efficacy. It provides some protection against sexually transmitted diseases. Patients should know about emergency contraception in case of a broken condom. Two tablets of 0.75 mg of Levonorgestrel pills are administered within 72 hours of unprotected intercourse. Considering the above mentioned issues, unplanned pregnancy should be avoided by proper use of effective contraception.
\n\t\t\tChronic kidney disease affects reproductive and sexual functions in both sexes. Although adequate dialysis will improve this dysfunction to some extent, but successful kidney transplantation has a better impact on fertility and reproductive functions.
\n\t\t\tReproductive success is a common, expected outcome for male and female recipients of kidney transplant. One of the most impressive aspects of successful renal transplantation in the young person is the ability of the male patient to father a child and the female patient to give birth to a healthy baby. There are, however, important maternal and fetal complications that need to be considered to provide optimal care to the mother and her infant.
\n\t\tPseudomonas aeruginosa, a Gram-negative pathogen usually found in the hospital, plays a crucial role for nosocomial infection and are also responsible for acute and chronic infection. P. aeruginosa is ubiquitous in nature and shows a great susceptibility against various classes of antibiotics [1]. The bacteria get colonize on any surface that contains water and multiply rapidly, carry out all the metabolic functions for growth and development which is an association of complex matrix known as a biofilm [2, 3]. The study predicted that a biofilm makes the bacteria more susceptible in the conditions like antibiotics, exposure in UV light and salinity [4]. Further understanding of the pathogenesis and resistance mechanism is a diverse area of investigation. Due to the complex biofilm forming ability, Pseudomonas species shows a great resistivity to various classes of antibiotics which are used to persistently overcome the microbial infection. The occurrence of Pseudomonas species in the hospitals helps to form the biofilms on the medical instruments (surface only) and other similar devices along with the implants in the patients [5, 6]. Pseudomonas species are used as a model organism for the study of biochemical mechanisms responsible for the susceptibility of the pathovars against a wide variety of antibiotics groups like amikacin, gentamicin, carbapenem, ofloxacin, ciprofloxacin, tigecycline, tobramycin and norfloxacin [7, 8].
The development of resistance by the pathogenic Pseudomonas species devise a major problem in the bacterial diversity by altering the genome sequences and the expression of proteins that ultimately improves the resistance of the pathovars [9, 10]. Various biochemical pathways and channel protein functions are affected due to the resistance of the bacteria [11, 12]. At this alarming stage of the scenario in details studies and prevention measures at an earliest is essential to control the same else in near future it may reach beyond our control. Therefore, the present chapter emphasizes on the infections due to Pseudomonas aeruginosa, their mechanism of infection and resistance to various classes of antibiotics.
The infectious diseases caused by P. aeruginosa are sometimes fatal for humans as it is a potential threat to people having less immunity like newborns, diseased persons and veterans. Notably, patients suffering from the diseases like cystic fibrosis, urinary tract infection, burn of the skin, leukemia, HIV-AIDS, diabetes, patients having longer stay in hospital environments and persons having organ transplantation are highly susceptible to P. aeruginosa. Table 1 listed the disease, symptoms and its causes.
Disease caused in humans | Symptoms | Adverse effects on human | References |
---|---|---|---|
Bacteremia | Fever, fatigue, chills, joint and muscle pain | Increasing bacterial population in the bloodstream | [13] |
Pneumonia, sinusitis | Fever, chills, difficulty in breathing, cough with or without sputum production | Deposition of liquids in the parts of the lungs. Swelling and inflammation of the nasal tract | [14] |
Folliculitis | Abscess production in the skin, redness of the skin, draining wounds | Inflammation of the hair follicles by bacteria | [15, 16] |
External ear canal Infection (otitis externa) | Ear pain, swelling, itching inside the ear, discharge from the ear, sometimes difficulty in hearing | Frequent showering leads to deposition of water and hence the growth of bacteria takes place at that location | [17, 18] |
Corneal inflammation (keratitis) | Redness, pain, swelling, inflammation, pus formation, impaired vision | The bacteria adhere to the lens and other parts of an eye within 24 h of its exposure by its cilia and flagella and forms the biofilm | [19, 20] |
Urinary tract infection | Burning with urination, cloudy or bloody urine, strong odor, rectal pain (in male), pelvic pain (in female) | The transfer of bacteria into the urethra | [21] |
Diabetic foot | Swelling of foot and ankle, dry cracks in the skin(around the heel), corns or calluses | Tissue damage in the foot and severe pain due to ingrown toenails | [22] |
Diseases and symptoms of Pseudomonas aeruginosa infection.
The resistance of P. aeruginosa to different aminoglycoside agents show a tremendous threat to public health as well as constrains the therapeutic choice available. The use of multiple drugs against the diseases in a low dose make the P. aeruginosa strains more resistant to a wide range of antibiotics [23]. The different strains of P. aeruginosa showing resistance to various antibiotic classes along with the pathway of resistant have been demonstrated in Table 2.
SI no. | Strains of Pseudomonas aeruginosa | Showing resistance to antibiotic class | Mode of action | References |
---|---|---|---|---|
1. | PA40, PA43 | Amikacin | Multi-drug-resistance (MDR) | [24, 25] |
2. | ATCC 27853, P2284 | Ticarcillin/clavulanate | Production of β-lactamase | [26] |
3. | K385 | Chloramphenicol and norfloxacin | Overexpression of mexC-MexD-OprJ operon | [27] |
4. | PA-M4 | Ciprofloxacin | Overexpression of MexEF-OprN operon | [28] |
5. | OCR1 | Gentamicin | Overexpression of MexAB-OprM operon | [28] |
6. | PAO4222 | Carbapenem (imipenem and meropenem) | Loss of porin channels in the outer membrane, expression of OprD and secreting carbapenem-hydrolyzing metalloenzyme | [29] |
7. | PAO4098E | Carbenicillin and tobramycin | Inactivation of aminoglycosides enzyme, ribosomal methyl group transferase enzyme | [27] |
8. | PAO1 | Tigecycline | Inhibition of MexXY-OprM activity | [30] |
9. | KG3002 | Ofloxacin | Inactivation of MexC operon | [31] |
10. | KG3000 | Ciprofloxacin | Expression of MexC-MexD-OprJ operon | [32] |
11. | PAO1 | Fluroquinolones | DNA gyrase topoisomerase IV activity | [33, 34] |
12. | PA1109 | Polymyxin E (colistin) | Modification in the LPS layer | [35, 36] |
13. | PA124 | Tetracyclines | Activation of MexXY-OprM efflux pump | [37] |
14. | PAO1 | Quinolones | Expression of MexEF-OprN efflux pump due to mutation of NfxB, NfxC and NalB | [38, 39] |
15. | ATTC 27853, K1178 | Cephalosporin | Overexpression of MexAB-OprM efflux pump due to the NalB mutation | [40] |
Antibiotics resistance in different strains of Pseudomonas aeruginosa.
The virulence property of P. aeruginosa is mainly due to the presence of factors like alkaline protease, elastase, pyoverdin, pyocyanin, exotoxins and cytotoxins. This virulence factors are commonly restricted to immunocompromised patients. The pathovars also produces a kind of exopolysaccharide known as alginate in patients having chronic respiratory infections. These alginate serves as the adhesive on the solid surfaces and also protects the bacteria from unfavorable environmental conditions [41]. The bacteria also produce alginate lyase enzyme which can cleave the polysaccharide into short oligosaccharide units it has been observed that both the biosynthesis and degradation process plays a vital role in the infection process [42, 43]. Presence of extracellular virulence factors and cell surface associated structures promotes its pathogenicity [44, 45].
P. aeruginosa binds to the ganglioside present in the host epithelial surface with the help of lipopolysaccharide and bacterial adhesins (i.e. type-IV pili and flagella). Type-IV also facilitates the bacterial movement along the host cell surface known as “twitching motility” which enhances the development of biofilm [46]. After the attachment to the host cell type III secretion system (T3SS) get activated and makes pore or a channel (i.e. translocon) on the cell membrane by injecting cytotoxic effector proteins into the cytosol of host cell [47, 48]. Mainly four different types of toxins are found in the P. aeruginosa sp. i.e. Exoenzymes S, T, U and Y. EXoS, ExoT and ExoU are responsible for N-terminal GTPase-activating proteinase (GAP) activity, C-terminal ADP-ribosyltransferase activity (ADPRT) and adenylate cyclase activity respectively [49]. It has been found that the ExoU is also a potent cytotoxin to cleave the host membrane phospholipid layers i.e. Phospholipase A2 (PLA2) activity. The ExoU initiates the inflammation by secreting the arachidonic acid for activating lipoxygenase and cyclooxygenase pathways and results the production of prostaglandins. P. aeruginosa secretes an Exotoxin A which is a type of ADPRT that causes cell death by inhibiting protein synthesis due to suppression of host elongation factor 2(EF2) [50]. The lipase and phospholipase of the bacteria dissolve the surfactant lipids and phospholipids of the host cell membranes. The blue-green pigment pyocyanin develops the oxidative stress in host cells by disrupting the host catalase and electron transport system (ETS) hence suppresses the phagocytosis activity of the host immune system [51].
The type-VI secretion system (T6SS) seen in case of P. aeruginosa facilitates the interaction of this pathogen with other organism and provides defence from other bacteria. The H1-, H2- and H3-T6SS are the three distinct T6SS observed in this pathovars. The H1-T6SS is being used for the physiological study of antimicrobial activity [52, 53]. The H2- and H3-T6SS plays dual role in the interaction with both prokaryotic and eukaryotic cell. The production of proteases degrades the covered mucin and complement systems which results the disruption of the tight junctions between the host epithelial cells. Then the bacteria spreads from one cell to others by secreting the phospholipase by damaging the cell membrane [54]. The release of pyocyanin and pyoverdin interfere with the electron transport pathways and redox cycling system of the host cells. LasA and LasB are the two types of elastases produced by P. aeruginosa, commonly responsible for the burn wound infection and acute lung infections. The LasA hydrolyze the penta-glycine bridge necessary for the stabilization of the peptidoglycan in the cell wall and the LasB is responsible for the opsonisation of the lung surfactant proteins A and D [55].
A wide group of P. aeruginosa strains are resistance to various classes of antibiotics or antibacterial agents that makes it difficult to control the infection. The resistance in Pseudomonas species is broadly due to the below detail explained methods studied previously. Figure 1 explicitly elaborate on various mechanism of P. aeruginosa resistance. The resistance pattern and mechanism behind the development of resistance in the Pseudomonas species are the topic of interest for the researchers as it will help to develop the polyprophylactic procedures and mitigation of infection due to P. aeruginosa.
Resistance of P. aeruginosa to various antimicrobials as (1) shows the enzymatic modification, (2) impermeability resistance, (3) efflux system and (4) modification in the outer membrane.
P. aeruginosa consists of elements generally termed as transposons which induce resistance due to the modification of aminoglycoside enzymes. The infection due to the pathogen is usually combated by various class/groups of aminoglycoside antibiotics like kanamycin, gentamicin, streptomycin, amikacin and neomycin. Previous studies elucidate that, there are three types of enzymatic conformational change which are accountable for the resistance against the bactericidal compounds. These are phosphorylation of aminoglycoside phosphoryl transferase (APH) [56, 57] adenylation of aminoglycoside nucleotidyl transferase (ANT) and acetylation of aminoglycoside acetyl transferase (AAC) [58, 59].
The conformational modification and phosphorylation in the 3′-OH group is carried out by the APH enzyme. APH (3′) family of enzymes shows resistance against streptomycin, butirocin, amikacin, kanamycin and neomycin by encoding the genes such as aphA and hpaA which are involved in the metabolism of 4-hydroxy-phenylacetic acid (4-HPA). However, APH (2″) shows resistance to tobramycin and gentamycin classes of antibiotics. Due to adenylation of ANT enzymes P. aeruginosa increases resistance towards tobramycin, gentamicin, streptomycin, isepamicin and amikacin [60, 61]. The family of enzymes such as ANT (2″), (3″) and (4′) also shows a similar type of resistance in different strains of P. aeruginosa isolated from hospitals and intensive care unit (ICU) premises [62]. The N-terminal positions (1, 2′, 3 and 6′) of the (AAC) shows the enzymatic acetylation. Amongst various families, AAC (3-I), (3-II) and (3-III) are also resistant to gentamicin, tobramycin and kanamycin antibiotics respectively [63]. Apart from that AAC (6′) family of enzymes contributes to the resistance along with akamicin [64].
Impermeability to various exocompounds in Gram-negative bacteria is due to lipopolysaccharide (LPS) present in the cell wall. LPS is made up of lipid A, oligosaccharide core and O antigen regions which are linked covalently [65]. The lipid A region is hydrophobic in nature and made up of a disaccharide of glucosamine which is phosphorylated and helps in the anchoring of LPS to the cell membrane. The core oligosaccharide is accumulation of sugar, ethanolamine, phosphate and amino acids and can be divided into inner and outer core. The O antigen is the outer domain of bacterial LPS made up of repeating glycan polymers and attached with the core region. It has been observed that the deletion of lipid A makes the bacteria susceptible to various classes of hydrophobic antibiotics and degradation of O side chains determine the smoothness and roughness of the LPS [66, 67]. The use of ethylenediaminetetraacetic acid (EDTA), some organic acids like lactic acid and citric acid are found to alter the impermeability of the Pseudomonas species. These chelating agents can neutralize the negatively charged oligosaccharide core by binding with the (Mg2+) cations in the LPS molecule and promotes the removal of LPS molecules [68]. The accumulation of aminoglycoside level decreases in the case of P. aeruginosa leading to low uptake and hence shows impermeability resistance which has been reported in the strains isolated from the cystic fibrosis patients [58]. Similarly, tobramycin resistance due to impermeability was seen when studied for endocarditis in case of rabbits.
The drug efflux system in bacteria includes three major components i.e. outer membrane channel-forming protein (OMF), resistance nodulation division (RND) which helps in drug-protein antiport process and the membrane fusion protein that acts as a periplasmic link between above two components [69]. The mexXY operon codes the inner membrane protein (i.e. MexY) and periplasmic protein (i.e. MexX). Resistance nodulation division (RND) involves the MexXY efflux system which develops the resistance in Pseudomonas species [70, 71]. MexAB-OprM shows resistance against ticarcillin, broad-spectrum cephalosporin and β-lactam of clinical isolates, while the combination of MexAB-OprM, MexCD-OprJ and MexXY-OprM shows the carbapenem resistance [72]. The bacterial isolates like Burkholderia pseudomallei and Escherichia coli involve the three component systems known as RND type aminoglycoside efflux system. Treatment with ofloxacin and gentamicin increases the level of MexXY expression in case of mutants compared to wild-type strains [73, 74]. The wild-type of strains of Pseudomonas is resistance to the antibiotic classes like tetracyclines, aminoglycosides, glycylcyclines and erythromycin but the MexXY can express in presence of diverse class of antibiotics like lincomycin [75], macrolides [76], fluoroquinolones [77], chloramphenicol [30], β-lactams [72], novobiocin [78] along with the wild type of antibiotic classes. In the reduced aminoglycosides condition both adaptive and impermeability resistance in the Pseudomonas sp. is expressed. The expression of MexXY gene is regulated by mexZ repressor, present in the upstream region of MexXY region of the gene and belongs to tetracycline repressor protein (TetR) and AcrR repressor protein family [79].
The exoskeleton of the Gram-negative bacteria is present to resist against the adverse environmental conditions. Likewise, the outer membrane of P. aeruginosa is designed in such a way that it can permit small hydrophilic molecules and inhibit larger molecules such as antibiotics [80]. Due to the crucial arrangement of aquaporin proteins in the cell membrane, the small hydrophilic antibiotics of quinolone and β-lactam classes can pass through the outer membrane. P. aeruginosa strains produce four major aquaporins (i.e. oprP, oprD, oprF and oprB) and two minor aquaporins (i.e. oprC, oprE) whereas the mutant strains lack oprF [81, 82]. The oprD is a specialized porin molecule present in bacterial membrane that helps in the process of up-taking positively charged amino acids like arginine and lysine [83]. The minimum inhibitory concentration increases due to the loss of oprD porin from the outer membrane of the Pseudomonas sp. thus increasing the resistance to imipenem class of antibiotics [84]. As the porin channels are impermeable to the polymyxin E and aminoglycoside, these molecules bind with the LPS present in the outer membrane, destructs the barrier and allows the antibiotics to enter into the bacterial cells [85]. Through this mechanism the aminoglycosides can enter into the cytoplasm of the bacterial cell and disturb the protein synthesis process in the ribosomes that kills the bacteria simultaneously. But the overexpression of the oprH an outer membrane protein [86], prevents the binding of antibiotics to LPS making it resistant for laboratory strains of Pseudomonas species.
Bacterial communities aggregate themselves to a substratum and encapsulated in a proteinous polysaccharide of matrix evolved during adverse environmental condition such as various irradiation treatments and therapy which is known as biofilm. Mostly these polysaccharide/polymeric matrix leads to the formation of biofilms over a water surface and shows resistance and enhances their survivability against the antimicrobial agents [87, 88]. The formation of biofilm is predominantly found in case of various biomedical instruments such as catheter, implants, ventilator and dialyser used patients residing in the hospital [89]. The bacteria are found to evade from host immune response due to the formation of biofilms and helps in promoting collateral damage to the tissues. Only few antibiotic classes act as an effective bactericidal agent for the free-floating bacteria but it fails to act against the bacteria forming biofilms as the biofilms are 1000 times more invulnerable to it [90, 91]. During environmental stress conditions, the bacteria change from free-living unicellular form to the planktonic form and then to the attached biofilm structure which enables the survivability of the bacteria. The matured biofilm starts to segregate from a place and develop an immobile structure in the new surfaces for colonization [92, 93]. The chemical therapy of antibiotics was not effective as the molecules cannot penetrate into the complex biofilm matrix due to the production of cover like exopolysaccharides matrix known as glycocalyx [94, 95]. Mostly the pathovars of P. aeruginosa forms the biofilm in the dialysis membrane and restricts the diffusion of piperacillin antibiotic into the complex aggregation [96]. It is pertinent to mention here that the bacterial biofilm is resistant to various classes/groups of antibiotics.
The P. aeruginosa has been found to be resistive to various bactericidal agents and mainly infects to the people suffering from HIV-AIDS and cancer due to the compromised immune system, use of broad-spectrum antibiotics for a longer duration and dependency on life support medical devices like a catheter, ventilator and dialyser. The bacteria communicate with each other by secreting extracellular signaling molecules known as autoinducer. The autoinducer level is directly proportional to the growth of bacterial population, hence with the increase in bacterial population the accumulation of autoinducer in the environment is at the peak [10, 97]. This process of production, release of signaling molecules is termed as quorum sensing.
There are four types of quorum sensing pathways discovered for the P. aeruginosa species which includes the LasR and LasI, RhlR and RhlI, PqsR-quinolone controlled system and the integrated quorum sensing (IQS) system which works under limiting conditions of phosphate [98, 99]. The formation of complexes of LasR with 3-oxo-C12-HSL activates the LasI synthase gene which helps in the process of autoinduction. The LasR complex regulates the expression of rhlI and rhlR genes along with the PQS systems which are related to the second and third mode of quorum sensing system of pathway respectively. The activation of its own regulon by the binding of C4-HSL with RhlR induces the second induction processes. The activation of RhlR is induced by PqsR-PQS complex which regulates the three modes of signaling in Quorum sensing along with inhibits the expression of the pqsR and pqsABCD. The ratio of 3-oxo-C12-HSL to C4-HSL gives an idea about the activation of PQS [100, 101]. The virulence property of P. aeruginosa is controlled by the RhlR along with C4-HSL and PqsR or LasR. Incase of the isolates of P. aeruginosa from the cystic fibrosis patients the mutations in the LasR supplies the autoinducer as there is the necessity of phosphate starvation protein (PhoB). This LasR activates the expression of pqs genes by the production of IQS which expresses the rhl gene hence shows the pathogenicity [102].
Pseudomonas species also include the resistance mechanism like adaptive resistance, acquired resistance and intrinsic resistance which further helps in the increasing the resistivity of the pathogen to a wide range of antibiotic class.
The resistance which is dependent on the physical and chemical stresses, growth states and promotes the initiation of the regular processes inside the cell in the presence of antibiotics and reverts back to the primary condition in the removal of the inducers are known as adaptive resistance [103, 104]. Previous research studies manifested that the resistance is due to many factors like the use of sub-inhibitory concentration of antimicrobial agents, polyamines, heat shock, SOS response, pH imbalance and anaerobiosis condition [105, 106]. P. aeruginosa was found to develop adaptive resistance against divalent Ca2+ and Mg2+ ions and the polymyxins which are controlled by PmrAB and PhoPQ pathways [107]. P. aeruginosa gradually reduces susceptibility in the presence of antibiotics and is altered in absentia this phenomena are reversible in nature and scientifically termed as the adaptive resistance [108]. The extensive studies revealed that adaptive resistance can also be developed in both in vivo and in vitro conditions due to the administration of antibiotics into the bacterial culture for few hours and this resistance disappears after the removal of antibiotics from the media [109]. But it is observed that the organism shows resistance when there is a low accumulation of the aminoglycosides. The resistance induced through drug efflux system and due to the gene expression associated with anaerobic respiration. The bacteria were grown in the anaerobic condition and nitrate environment to check the accumulation and the uptake of aminoglycoside and found that P. aeruginosa is capable of showing resistance in the anaerobic conditions [110].
The acquired resistance involves the transfer of plasmids, prophages, DNA elements and transposons by means of transduction, transformation and conjugation. This horizontal transfer shows the β-lactam and aminoglycoside resistance in P. aeruginosa [111]. The chemical modification of the aminoglycosides alters the affinity of a 30S subunit of ribose sugar to the target. Antibiotic drugs like cephalosporin, carbapenem [112] and penicillin [113] help in the process of development of resistance property in case to P. aeruginosa [112]. The mutational resistance occurred due to the formation of biofilms and the action of DNA-damaging agents. The mutation frequency is found to be increased by 10-fold, greater than 100-fold and 70-fold if the resistance is caused by meropenem [85], ciprofloxacin and if any mutation in genes respectively [114]. The downregulation of antioxidant enzymes damages the DNA in the biofilms. The library screening of cystic fibrosis (CF) patients describe that there are various mutators play a significant role during the early infection stages, mutL and mutS are the hypermutators which are widely found. The mutation in genes mexR, mexZ and nfxB is due to the overexpression of MexAB-OprM, MexXY-OprM and MexCD-OprJ efflux pump respectively. OprD is a porin that suppresses the uptake of imipenem [115] and another antibiotic [116] leading to the clinical resistance. The ampC β-lactamase, AmpD mutate and controls the activity of AmpR regulator [117]. The P. aeruginosa clinical strain shows resistance to mutations in gyrase (gyrA) and gyrB as well as parC and parE. Overlay we can demonstrate that the mutations in the unrelated genes give rise to acquired resistance against different antibiotics.
The intrinsic resistance is due to the combination of the efflux system along with the β-lactamase and the low outer membrane permeability, the entry of antibiotic molecules through the outer membrane of the bacteria [8]. The increase in antibiotic concentration in the environment helps in the low permeability of the outer membrane permits the entry of larger compounds and antibiotics into the cell with the help of porin protein channels and makes the bacteria resistant this slow process helps in increased resistance of the organism [83, 118]. The intrinsic resistance is carried out by the help of multi-drug efflux systems like MexAB-OprM and MexXY-OprM operon along with the inactivation of enzyme β-lactams by hydrolysis [119, 120].
The low membrane permeability, overexpression of efflux pump and deletion of porin channels are the cause behind the resistance of Pseudomonas species. P. aeruginosa was predominantly found in the ICUs of European continents hence put in the list of “ESKAPE” pathogens by the Infectious Disease Society of America [121, 122]. The existing antibacterial agents are not effective against these isolates and hence a severe threat for public health. A study in China for the bacterial resistance surveillance demonstrated that the resistance in case of hospital-acquired infection (HAI) is prevalence than community-acquired infection (CAI) [123]. Relatively few studies explained about the outbreak of Multi-drug resistance (MDR) in P. aeruginosa species. The worldwide study of Pseudomonas infections gives us the idea that in the year 2002 14% and in 2003 9.9% resistance were found in ICU isolates and nosocomial infections in United states [77]. During 1997–1999 8.2% and 4.7% of resistance were due to nosocomial infections in South America and Europe respectively [124, 125]. In 2001 2.8% and in 2005 6.9% of resistance were due to nosocomial infections in Japan [126] and Malaysia [127].
The National Nosocomial Infection Surveillance System (NNIS) also conducted the study for statistical analysis of the resistance developed by the hospital strains of P. aeruginosa and define that the hospital samples are more resistive to various groups of antibiotic classes [128]. The resistance to various classes of antibiotic by P. aeruginosa is a new threat to our defence system as once compromised it will be a difficult task to control the spread and infection of the bacteria among the living system. It has been also reported that the bacteraemia was not in control by the administration of antibiotics as it was spread by the antibiotic-resistant strains of P. aeruginosa [129].
Due to hospitalization for a significant period of time in the ICU [130] of a patient suffering from respiratory disorder [110], kidney disease [89] and other diseases which needs the ventilator along with the medical device installation are more prone to the infection of P. aeruginosa [131]. The administration of various drugs makes the Pseudomonas strain more resistive due to mechanisms like multi-drug-resistance (MDR), efflux systems, and loss of porin proteins from the outer membrane. Extensive research work is necessary to understand the infection mechanism and the development of resistance in the bacteria, the suitable combination of antibiotic molecules which will overcome the resistant behaviour and eradication of the bacterial biofilm without affecting the other processes in the living beings.
The eradication of the resistance is highly necessary for the prevention followed by cure to Pseudomonas infection for healthy sustenance. So, research is still going on to overcome the resistance by the organism and combinational therapeutic approach is found to be an effective tool against the resistance of the Pseudomonas species.
Cross-infection through hospital personnel gives rise to 30–40% of infection so irrespective of cost and time use of masks, cloths, gloves, antiseptics for the proper isolation can minimize the resistant developed in the pathovars [132]. It was observed that usual laboratory methods failed to detect the Antimicrobial-Drug resistance hence new testing methods, standards and guidelines implemented by various national and international clinical research groups for the early detection and control its outbreak [133]. The synergistic of two or more anti-bactericidal molecules is found to be an effective than monotherapy to overcome the resistance. The combination of polymixin with tobramycin is found to be an effective antimicrobial for inhibition in the formation of biofilms [134]. The combinational administration of tobramycin with aminoglycoside and macrolide clarithromycin shows a devastating effect against the biofilm [79]. Likewise, the integration of azithromycin with the tobramycin helped to destroy the bacterial biofilm when treated with in vitro condition [135].
The use of nitric oxide (NO) was reported to trigger the downstream of signal processing in quorum sensing and hence the production of cyclic-di-GMP decreases hence the extracellular matrix of biofilm get destroyed [136]. The introduction of deoxyribonuclease (DNAse) directly into the biofilm of the bacterial colony as it digests the environmental DNA (eDNA) enzymatically. The P. aeruginosa contains a molecule known as acyl-homoserine lactones (AHL), the blockage of signaling of this molecule prevents the formation of biofilms [137]. The rsaL gene expression acts as a negative regulator of the lasI gene expression which is responsible for the quorum sensing in the strains of P. aeruginosa [138]. The PmrAB and PhoPQ can alter the permeability of the outer membrane as the level of divalent ions decrease it increase the extracellular DNA in the biofilms and shows resistance to cationic bactericidal peptides and polymyxins [139]. Due to this phenomenon, the addition of amino arabinose to the 1st and 4th phosphate position in lipid A of the LPS and the net negative charge neutralized and the cations can enter into the bacterial cell [140].
The medical equipment and the biomaterial use for implantation purpose are coated with silver which reduces the adherence and biofilm producing ability of the bacteria. The novel compounds like curlicides and pilicides have been reported to inhibit the role of adhesin molecules and hence reduces the formation of biofilms on the surfaces. The use of nanomaterials of graphene and zinc as the coating of biomedical implants are found to be effective against the biofilm formation [141]. In some instances, it is necessary to replace the device after prolonged use with the patient/s. The small molecular artificially engineered peptide 1018 was discovered with the anti-biofilm activity [142].
The pharmaceutical industries are working towards the development of vaccines to tackle the antimicrobial resistance and few are under clinical trials which are believed to be effective against the resistance [143, 144]. There are several vaccines such as polysaccharide-protein conjugates, LPS-O antigen, OprI and OprF membrane protein, live-attenuated, flagella and DNA vaccines are known to be invented for the control of antimicrobial resistance of P. aeruginosa. But the recombinant vaccine IC43, OprI and OprF and flagella vaccines are found effective and are under clinical trials for cystic fibrosis patients [145]. Apart from the above various NGOs and educational groups are playing a great role to educate the students, doctors, hospital personnel and society by making people aware about the use of proper dose and medicines by consulting the physician along with the maintenance of hygiene in the surroundings.
P. aeruginosa as an emerging human pathogen causes an array of diseases in immunocompromised patients, newborns as well as healthy persons. The infection as a biofilm is much more severe than monoculture. Various antimicrobial/antibiotics treatment leads to not only increases the resistance in different strains of P. aeruginosa but also increase the disease incidence. The present chapter clearly enlightens various mechanisms of infection of P. aeruginosa, its biofilms and resistance pathways/mechanisms, global impact due to infections which further paves the way for various remediation in future through improved implementations of genetic engineering and advances nanotechnology tools.
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