\r\n\t
\r\n\tIt is second only to malaria, of the parasitic infections worldwide. Species of Schistosoma that infects humans are: Schistosoma mansoni and Schistosoma intercalatum which causes intestinal schistosomiasis. Schistosoma haematobium which causes urinary schistosomiasis, Schistosoma japonicum and Schistosoma mekongi which causes Asian intestinal schistosomiasis. Other important digeneans are : Fasciola hepatica and Fasciola gigantica (Liver flukes), Dicrrocoelium dentriticum ( Lancet liver fluke), Fasciolopsis buski, Opisthorchis sinensis (Chnese liver fluke), Paramphistomum species ( Stomach fluke), Paragonimus specie ( Lung fluke).
\r\n\tThis book will intend to review the prevalences, epidemiology, pathogenesis, prevention, and control of these parasitic flukes albeit described as neglected tropical diseases. The control of parasitic flukes is nevertheless crucial and worthy to be considered.
",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:"bbf3a6f07496bd1b2454c067013b4268",bookSignature:"Associate Prof. Omolade Olayinka Okwa",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9620.jpg",keywords:"Epidemiology, Flukes, Schistosoma, Snail Host, Opisthorchis Sinensis, Fasciolopsis Buski, Fascioliasis, Liver Flukes, Gastrointestinal Disorders, Haematuria, Intestinal Flukes, Ivermectin",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 3rd 2019",dateEndSecondStepPublish:"March 18th 2020",dateEndThirdStepPublish:"May 17th 2020",dateEndFourthStepPublish:"August 5th 2020",dateEndFifthStepPublish:"October 4th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"99780",title:"Associate Prof.",name:"Omolade Olayinka",middleName:null,surname:"Okwa",slug:"omolade-olayinka-okwa",fullName:"Omolade Olayinka Okwa",profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Lagos State University",institutionURL:null,country:{name:"Nigeria"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@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. 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A functioning vascular access (VA) represents a key issue in the management of patients needing acute or chronic hemodialysis (HD). However, VA surgeons, interventionists and all involved in VA creation and preservation are facing an everyday challenge, a huge one: How to meet their HD patients’ VA needs. Most centers over the world are currently taking care of a steadily increasing and aging HD population, with more and more comorbidities, particularly diabetes mellitus, as well as of a growing proportion of prevalent patients with history of multiple access failures. With help of both autogenic and graft materials it has been possible to develop up to the present a wide armamentarium of VA options. However, all access alternatives are plagued with the same problems as in the past decades: thrombosis, infection, steal, etc, all of which limit their time span. In addition, anatomic sites for access creation are limited and may become exhausted. Every VA that fails brings the patient one step closer to a terminal access problem, a point where all roads seem closed. To avoid reaching this point, every VA team should be able, through careful planning and systematic application of adequate techniques for VA creation and preservation, to reduce VA-related complications to a minimum. In this chapter, a general overview of the field of VA for chronic hemodialysis in adult patients is offered where the most relevant topics are mentioned and briefly discussed. It is by no means an exhaustive review but we hope this way to convey an idea of the magnitude and complexity of the VA-related problematic and their possible solutions. We have dispensed with including details of VA history since a lot of well documented work on this issue is available in the literature.
\n\t\t\n\t\t
Temporary access in current nephrological praxis is synonymous with double lumen catheters whose main goal is to serve as interim VA. Emergent HD in a patient with chronic kidney disease (CKD) is the commonest indication for HD catheter insertion. It is a known fact that in most countries over the world a significant proportion, if not the majority of CKD patients starting HD do not have a functioning PVA [1]. Some of the reasons for this trend are:
\n\t\t\tmany patients seek specialized medical care for the first time when frank uremic symptoms are present,
late referral to either a nephrologist or
to the access surgeon, etc, which do not allow for a permanent VA to be timely created.
Two types of double-lumen catheters are used for emergent acute or chronic HD:
\n\t\t\tnon-tunneled, uncuffed (NTC) also called acute or temporary catheters, and
Tunneled, cuffed catheters (TC, called “permanent” catheters).
NTC are still the most commonly used catheter type for emergent HD and can be readily inserted, exchanged and withdrawn either at bedside or in a procedure at any center or outpatient dialysis facility. Although NTC are deemed to be used for a short dwell times (< 3 weeks), in some centers they are used for extended periods. Eventually, they are even exchanged for up to 2 times in case of malfunction [2].
\n\t\t\t\tTypical NTC insertion method is the Seldinger technique, which consists in placing a catheter percutaneously through a guidewire [3]. Once inserted, the NTC should be firmly fixed to the skin by means of a monofilament nonabsorbable synthetic suture (polyproplylene or nylon). Multifilament, also called “braided” sutures like silk, should not be used because bacteria may hide within the interstices of the braids and this way the catheter entry site may become secondarily infected. A loose fixation of the catheter to skin causes a constant in- and outward movement of the catheter through entry site which favors bacterial colonization and infection. Dehiscent sutures lead to partial or total catheter extrusion. In case of partial extrusion, no attempt should be done to reintroduce the catheter but rather, if deemed safe, it may be exchanged over a guidewire.
\n\t\t\t\tThe preferred insertion site is the right internal jugular vein (IJV) mainly because in a great majority of cases it does not interfere with ulterior AV access creation on the ipsilateral upper extremity [4]. On the contrary, catheterization of the left IJV is not equally safe as the right one and is associated with left innominate vein stenosis or thrombosis [2,5]. Femoral veins are safer vein accesses in emergency settings particularly in patients with high risk of bleeding [6]. However, when left in place for extended periods, femoral catheters may lead to stenosis and thrombosis of the external and/or common iliac veins causing significant impairment of venous drainage of the lower limbs with mild to severe, painful edema. In transplantation candidates, external iliac vein thrombosis, which can extend up to common iliac vein may preclude ulterior renal graft placement on the affected side. With respect to subclavian vein approach, the KDOQI guidelines [7] strongly recommend its avoidance unless:
\n\t\t\t\t\tpermanent access creation on the ipsilateral extremity is not possible because of severe arterial occlusive disease,
all potential access sites on the side are exhausted, or
when there is no other option.
Subclavian vein stenosis or thrombosis are a sequelae of 20 to 50% of subclavian vein catheters, which usually preclude ulterior use of ipsilateral arm for PVA creation [4]. Endovascular procedures like balloon angioplasty or stenting have proved useful in restoring central vein patency [8].
\n\t\t\t\tReal-time ultrasound guidance decreases significantly the rate of puncture-related complications in the case of IJV cannulation [9]. Landmark-guided puncture may be an acceptable alternative in experienced hands. Regardless of the employed insertion technique, in patients with history of previous IJV catheterization, checking sonographically for IJV patency (Figure 1) before making any catheter insertion attempt is strongly advised.
\n\t\t\t\t\tA) Normal ultrasound appearance of the right internal jugular vein (RIJV). (B) RIJV damage after catheterization.
(for superior vena cava catheters) or an abdominal plain film ( for femoral catheters) should be done to verify catheter tip position. Ideally, both posteroanterior and lateral thorax views may be needed to better assess catheter location. Normally, catheter tip should lie at the junction of the vena cava with the right atrium so that the catheter side openings are located into the caval lumen (Figure 2). Catheter malposition (Figure 3) and puncture-related complications can also be readily diagnosed with chest radiographs in two views.
\n\t\t\t\t\tA) Posteroanterior chest X-ray showing normally located right-sided internal jugular vein catheter. (B) Normal lateral view of the catheter (arrows).
A) Abnormal location of a left-sided internal jugular vein catheter. Lateral thorax view (B) shows catheter tip (arrow) and side openings into the azygus vein.
The distance from insertion site to venoatrial junction may vary according to patients anatomy (height, obesity), thorax length and shape, central vein configuration and insertion route. However, as a rule of thumb, a catheter of 15-16 cm in length catheters may be adequate when placing right-sided internal jugular veins in adults. A 17.5-20 cm long catheters is required for either left internal jugular or left subclavian vein approach [10]. Femoral catheters should be 20-25 cm in length depending on insertion point and patient’s physiognomy (i.e. obesity).
\n\t\t\t\tNTC malfunction may be due to non-thrombotic causes like catheter misplacement, kinking, use of inappropriate catheter length and formation of pericatheter fibrin sleeve [11]. Thrombotic catheter occlusion is usually due to either intraluminal and/or mural thrombus formation. Malfunctioning catheters, except those having a fibrin sheath, mural thrombus or some evidence of infection can be exchanged over a guidewire. Biofilm formation begins immediately after catheter insertion by bacteria that has being carried by the catheter surface from skin entry site. With time, biofilm turns into a fibrin sheath o sleeve that covers side openings and adheres to the entire external surface of most catheters [12]. In advanced stage, a total extraluminal encasement of the catheter occurs causing backflow of blood which goes out through the catheter insertion orifice when dialysis pump is started. Thus, bleeding through catheter entry site only during HD indicates the presence of a fibrin sleeve and, the catheter should be removed. However, much of the fibrin sleeve may remain adhered to the vein wall after catheter removal [13] (Figure 4).
\n\t\t\t\t\tCatheter tip with adhered fibrin sheath.
Catheter exchange after balloon disruption of the sleeve has been reported to be a successful procedure in such cases [12]. Too short left-sided IJV or subclavian catheters may cause catheter malfunctioning as tip and side openings will lie within the lumen of the left innominate vein whose caliber and flow are lower than that of the vena cava [8].
\n\t\t\t\tCentral vein catheterization in patients with ESRD bears a higher risk of bleeding because of disturbances in platelet adhesion and aggregation. Carotid artery puncture can lead, if unadvertent, to formation of a big hematoma which can further extend in the neck and upper mediastinum causing external airway compression [14]. Mediastinal hematoma is a rare but feared complication after unadvertent arterial puncture. Pneumothorax, hemothorax and chylothorax are complications more related to subclavian than to IJV cannulation. Femoral artery puncture can also lead to formation of huge hematomas at the groin. Retroperitoneal hematoma is also an extremely rare complication and results from inadequate puncture technique.
\n\t\t\t\tBleeding around catheter entry site is most commonly due to a wide skin opening. Applying compression at entry site with sterile dressing may suffice to stop bleeding. Otherwise, the orifice can be reduced by stitching with 6x0 nylon suture which is usually effective to achieve local hemostasis. To prevent this complication, the size of the skin incision must be tailored as small as possible so that the catheter, once in place, fits tightly in the orifice. Persisting bleeding with bulging at puncture site points at a more serious cause of the bleeding and the patient should be immediately evaluated by a vascular surgeon. As mentioned before, bleeding only during HD is highly suggestive of encasement of the catheter by a fibrin sheath.
\n\t\t\t\tEarly infection of a new inserted catheter indicates poor aseptic conditions at the time of placement or inadequate catheter handling during HD or at home. Infected catheters may be the starting point of bacteremia and sepsis and there is an increased risk of metastatic complications, including endocarditis, septic arthritis, and epidural abscess. The relative risk of bacteremia is 7-fold higher in CKD patients with catheters than in those with an autogenous PVA [15]. Staph aureus and other grampositive bacteria like coagulase-negative staphylococcus and enteroccocus are the most commonly isolated agents in infected catheters [16]. Cultures of blood, entry site exudate and catheter tip play a key role in identifying the causative agent. Sensitivity tests to different antimicrobials with determination of minimal inhibitory concentration (MIC) are the basis for an effective antibiotic treatment.
\n\t\t\t\tDespite improved catheter technology and better biomaterials, central vein stenosis continues to be the most serious middle- and long-term complication of HD catheters. Central vein stenosis may preclude permanent VA creation on the ipsilateral upper or lower extremity. Clinically, the development of superficial vein collaterals on the affected side or the development of limb swelling after ipsilateral arteriovenous access creation shoul raise the suspicion of central vein occlusion. This diagnosis can be confirmed by imaging procedures like angiotomography or MRI. In the past decades, endovascular procedures like percutaneous transluminal angioplasty (PTA) or percutaneous transluminal stenting (PTS) has proven useful and safe to recanalize occluded central veins with low rates of technical failure. However, multiple additional interventions are the rule with both treatment modalities since neither of them offer truly durable outcomes nor add to the longevity of the ipsilateral access [17]. Superior vena cava syndrome is an extreme manifestation of central vein stenosis and results from multiple catheter insertions [18]. Femoral vein catheters may cause stenosis and thrombosis in the femoro-iliac axis precluding kidney graft placement on the affected side.
\n\t\t\t\tare usually of iatrogenic origin. Some of them can close spontaneously. US guided compression has proven effective some cases. If ineffective, a more invasive treatment should be attempted. The standard approach has been surgical but currently, percutaneous endovascular implantation of covered stents has been reported to yield similar results while being less invasive [19].
\n\t\t\t\tTC are made either of polyurethane, carbothane (polycarbonate-based polyurethane) or silicone. They are available in many shapes (straight or pre-curved), sizes (12-16 Fr), lengths (16-50 cm from tip to cuff) and tip forms (rounded, stepped or splitted). In addition, they may consist of either two single lumen catheters as the original Tesio catheter, which has 2 independent 10F catheters [20], or a double lumen device. All are provided with a polyester cuff favoring tissue in-growth for fixation of the catheter into the subcutaneous tunnel. TC can be either placed de novo or in exchange for a nontunneled catheter using the same insertion site without increased risk of infection [21,22].
\n\t\t\t\tA detailed description of all technical aspects of TC implantation are beyond the scope of this chapter. In principle, TC implantation technique is similar to that of NTC but a subcutaneous tunnel is additionally created to lodge the external segment or extension of the catheter. Catheter placement can also be done at a procedure room within the HD unit. TC offer some advantages over NTC. Tunneling from the neck to an exit site at the right or left upper chest quadrant below the clavicle brings greater comfort to patients, catheter extensions can easily be covered by dressings, concealed by clothing and, in addition, TC are suitable for outpatient management and care [23]. However, their disadvanges are many and far outweigh their advantanges [24]. In this regard, it should be underscored that tunneling does neither prevent nor make less severe central vein occlusion, which is the most feared middle- and long –term complication of all HD catheters.
\n\t\t\t\tTC have been found to reduce the incidence of catheter-related bloodstream infection particularly when antibiotic lock is additionally used [25]. However, contrary to NTC, TC are not routinely withdrawn as first move in case of infection. Removal is only done in case of persistent infection or infection recurrence nonresponsive to antimicrobial therapy. Therefore, a major concern in such cases is the emergence of multidrug-resistant bacteria. Long-term indwelling TC are associated with five- to ten-fold increased risk of bacteremia and sepsis, significantly higher mortality risk, decreased likelihood of adequate dialysis, more frequent hospital admissions and more frequent need for access surgeries [26,27]. It is essential to have cultures with blood drawn from catheter lumen as well as from a peripheral vein. Catheter infection can be confirmed by isolation of the same agent in both samples, particularly if the UFC count is 4-fold higher in the luminal sample than in the peripheral blood sample. Initial empirical administration of broad spectrum antibiotics should be followed by specific antibiotics when sensibility tests with minimum inhibitory concentration (MIC) data are available.
\n\t\t\t\tDysfunctional TC due to thrombotic occlusion requires administration of thrombolytic therapy to restore flow, decrease venous dialysis pressure and increase dialysis delivery. Tissue-type plasminogen activator (tPA, alteplase), is currently the only recommended antithrombotic agent for failing TC [28]. Single intraluminal instillation (in 30- 60 minutes) of low-dose (1 mg/ml) alteplase has been shown to increase catheter flow with significantly more patients achieving Qb=300 ml/min than with urokinase (5000 U/ml) (70% versus 35%; P< 0.013) and completing an HD session (93% versus 70%; P =0.023) [28]. TC are used as definite access in patients who have exhausted all options for PVA creation, cardial failure, severe occlusive peripheral disease or those with limited life span. Exceptionally, TC may be placed in unusal locations, like inferior vena cava (Figure 5) or left atrium.
\n\t\t\t\t\tA) Tunneled catheter placed into the inferior vena cava. (B) Catheter being used for HD.
Preserving peripheral veins at both upper extremities (not only at the non-dominant side) as well as both subclavian veins is the mainstay for an ulterior successful PVA creation. The major veins of the upper extremity like the cephalic and basilic, eventually also the cephalic accessory, are the only appropriate vessels for creation of a fistula or graft and should not be routinely used for administration of fluid or medication, especially when irritating, because they may cause irreversible endothelial injury. Indiscriminate peripheral venipuncture is the first cause of loss of adequate veins for VA creation. Nursing personnel should be advised to use alternative veins like hand dorsum veins (Figure 6), the median or intermediate antebrachial vein and other minor forearm veins for intravenous fluids and medications. If there is some compelling need to use any of the major arm veins, cannulation should be done only for short periods of time, using small gauge needles, and rotating puncture sites to prevent phlebitis and thrombosis. Patients should ideally receive education about the importance of vein preservation.
\n\t\t\t\t\tPreventing damage of peripheral veins. Venous cannula in the cephalic vein of a CKD patient (A) is removed and placed in a hand dorsum vein ( B).
The exact timing of placement of VA should be determined in each particular case by the rate of decline of renal function, presence of co-morbidities (i.e. diabetes, obesity), estimated time from referral to surgeon until access creation and degree of difficulty for VA creation. Avorn et al [29] found that patients referred to a nephrologist 90 days before the initiation of dialysis were approximately 40% more likely to undergo catheter placement compared with those who were seen 90 days before the initiation of dialysis.
\n\t\t\t\tThe initial evaluation of peripheral veins is done on clinical grounds. Past access failure should be analyzed and a careful history of previous catheterizations, particularly of central outflow veins, like subclavian and innominate veins. Previous right IJV cannulation in most cases do not preclude ipsilateral access creation, except in patients developing arm edema during catheter dwell time or when enlarged superficial vein collaterals are observed on the chest wall or the neck, which is highly suspicious for significant central vein stenosis or occlusion. Evaluation of the arm veins should be done by palpation with a proximal tourniquet or inflatable pressure cuff in place. This way, stenotic or thombotic segments can be easily detected. The explored outflow vein walls should be distensible all along its course with uninterrupted lumen. Collecting past history of venipuncture, presence of edema, especially if unilateral, is extremely important. Palpation of the arteries should include assessment of pulse amplitude and rhythm, as well as texture of the arterial wall all along its course. Evaluation should detect wall hardening, plaques or absence of pulse. Allen’s test should be routinely done in all cases.
\n\t\t\t\tColor Doppler ultrasound (CDU) is usually a complementary diagnostic tool in the setting of VA planning. It should be used to further assess pathologic findings obtained at clinical evaluation. CDU can corroborate or exclude underlying vein stenosis and thombosis, arterial plaques, etc. Hemodynamic parameters like vessel diameter, arterial flow pattern and flow measurement can also be readily assessed. Minimum artery diameter for successful autogenous AV access creation at forearm ranges from 1.5 mm and 2.0 mm although 2.0 mm seems to be a more acceptable limit in adults [30,31]. In addition to measuring arterial diameter, it is of utmost importance to exclude calcification of the media, which precludes surgical opening of the artery, or the presence of proximal atheromas which would reduce inflow. Typical arterial flow pattern is shown in Figure 7.
\n\t\t\t\t\tDoppler ultrasound of the radial artery (A) showing nomal triphasic flow pattern (B).
Venous system can be evaluated sonographically for continuity and absence of strictures. To this end, CDU scans should be done with a distal tourniquet in place to distend the outflow vein. Evaluation of the basilic vein at upper arm is only possible with CDU since this vein is located below the brachial fascia in most of its upper arm course. Arm diameter in obese patients may limit access site selection. CDU may also dictate the need for primary or staged vein elevation in case of too deep lying outflow veins.
\n\t\t\t\tA central vein imaging procedure is necessary to exclude subclavian or innominate vein stenosis or thrombosis in patients with history of subclavian or left internal jugular vein cannulation, especially if catheter infection occurred or when vein collaterals are visible on skin over the chest. To circumvent the need for central imaging procedure, it is advisable to select in first instance the contralateral upper extremity for access creation, if the vessels are appropriate, in those patients with history of subclavian vein cannulation only on one side. Likewise, former left IJV cannulation requires that innominate vein stenosis or occlusion be excluded before ipsilateral VA creation.
\n\t\t\t\tThe sequence of VA creation should, ideally, be individually tailored with clear preference for native vessels, exhausting first more distal VA options bilaterally before considering creating a proximal one. The sequence of preference is:
\n\t\t\t\t\tradiocephalic fistula (RCF),
ulnarbasilic fistula (UBF),
brachiocephalic fistula (BCF)
brachiobasilic (BBF) or brachiobrachial fistula and
brachioaxillary straight graft (BASG).
Eventually, placement of a forearm graft, in preference in straight configuration, may be evaluated before moving to an autogenous upper arm access [32]. If graft placement is decided, the graft/vein anastomosis should be performed below the elbow crease in order that both cephalic and basilic vein at upper arm remain intact for ulterior access procedures.
\n\t\t\t\tSome basic clinical, hemodynamic and laboratory parameters should be systematically evaluated in patients scheduled for VA surgery [32]. Patients should be in their dry weight, afebrile without evidence of catheter infection or elsewhere, no signs of cardiac insufficiency nor pericardial effusion, normal range heart rate and rhythm, minimal BP 110/70 without orthostatic hypotension. Regarding laboratory data, normal WBC and platelet count with Hb levels above 8 g/dl are essential. Too high hematocrit levels can make the patient more prone to access thrombosis. In such cases, transient epoetin reduction should be considered. Coagulation tests like bleeding time, TP and TPT should be within normal range. Serum albumin should be 3.0 mg/dl or higher. Prothrombotic medication (methilprednisolone) should be tapered to 10-15 mg daily before performing access surgery. It is very important that antithrombotic agents (ASA, clopidogrel, davigatran), anticoagulants (low-weight heparin, warfarin) are stopped at least 5 to 8 days before surgery.
\n\t\t\t\tA detailed operative technique for each access type would be beyond the scope of this chapter. However, It can be never stressed enough that, for successful VA creation, surgical procedures should be done under stringent aseptic conditions, using appropriate surgical instruments, sutures and a meticulous technique. AVF not requiring general anesthesia, like forearm fistulas and BCF, may be performed on an outpatient basis in a procedure room located within a renal unit, Access procedures requiring axillary nerve block or general anesthesia should be performed in a conventional operating room keeping the patient hospitalized for a short observation period. Vein collaterals should be ligated to allow for better maturation. Ligation of tributary veins like hand dorsum veins in case of RCF and cephalic accessory vein in case of BCF may prevent retrograde flow once the runoff vein has enlarged and increased its flow. The recommended anastomosis technique for arm fistulas is side-to-end. However, for forearm fistulas, side-to-side anastomosis, turned into a functional side-to-end anastamosis by juxta-anastomotic ligation of the distal venous limb (Figure 8), may be an equivalent alternative which has an additional advantage: the anastomosis size can be tailored regardless of the diameter of the vessels.
\n\t\t\t\t\tSide-to-side anastomosis turned into a functional side-to-end by juxta-anastomotic ligation of the distal venous limb.
In case of BBF creation, subcutaneous transposition of the arterialized basilic vein is mandatory since it runs in most of its upper arm course beneath the deep fascia and would otherwise not be amenable to safe cannulation except in its short distal postanastomotic segment [33]. In addition, the basilic vein is crossed in part of its upper arm course by branches and filaments of the medial antebrachial cutaneous nerve. Aneurysmatic dilation of the postanostomic segment of BBF is commonly observed when superficialization is not performed owing to the fact that the arterialized vein is being “clamped” proximally by the deep fascia. Superficialization of the vein usually requires either a long incision or multiple short incisions in the medial aspect of the upper arm. However, a new endoscopically performed superficializacion technique has been described recently [34]. Some authors recommend doing superficialization as a two-stage procedure [35].
\n\t\t\t\t\tRCF (A) and BCF (B) with staged superficialization of the cephalic vein.
RCF, also called Cimino or Brescia-Cimino fistula, is by far the best type of HD access. It offers the longest and easiest to puncture vein segment, lowest venous dialysis pressures, higher primary function rates, as well as better long-term survival. Snuff box fistula, a distal variant of RCF which may be created at the basis of the thumb, can be performed if the caliber of the vessels at this location is appropriate. UBF, another autogenic VA type in the forearm, was first described by Hanson et al as early as 1967 [36]. UBF is an optimal VA alternative with good survival rates [37] which has not yet been included in the KDOQI recommendations probably under the argument that the posteromedial course of the basilic vein along the forearm is inconvenient for cannulation. However, in our experience, UBF does not need transposition to be successfully cannulated (Figure 10).
\n\t\t\t\t\tUlnarbasilic fistula being used for HD. Note that transposition of the arterialized basilic vein is not necessary for safe cannulation.
BCF and BBF with vein superficialization are the the two basic autogenic fistula variants at upper arm. If the basilic vein is found to be inadequate, one of the brachial veins may be used instead [34]. Other access options like Gracz fistula, or bidirectional (reverse) fistulas offer no additional advantages over other conventional fistulas [38].
\n\t\t\t\tIn the forearm, arteriovenous grafts (AVG) are placed in either straight or loop configuration [39]. Inflow artery of straight grafts may be either the radial or the ulnar artery. Inflow artery of forearm loop grafts is the brachial artery. Outflow veins are usually antecubital veins. As stated earlier, the graft/vein anastomosis should be located in preference below the elbow crease. At upper arm, the most common AVG variant is the brachioaxillary graft. Since adhesion between the graft and subcutaneous tissue may last up to 3 weeks, it is advisable waiting until after that time has elapsed to start cannulation. The shorter waiting time for starting cannulation is one of the advantages of AVG over AVF. The expanded PTFE (ePTFE) remains still the most commonly used graft material. Biological prostheses are of limited availability, usually more expensive and of variable size and quantity [39].
\n\t\t\t\tThey should be attempted only when all options in the upper extremity are exhausted.
\n\t\t\t\tIt is an autogenous AV access in the thigh which is created between the femoral artery and the transposed common femoral vein. It has good patency rates but a higher risk of distal ischemia [40].
\n\t\t\t\tIt is created by anastomosis of the distal femoral artery and the great saphenous vein (Figure 11) which is subcutanously transposed to allow cannulation. Access survival is acceptable [41].
\n\t\t\t\tIt is also an autogenous alternative whose inflow is provided by the proximal femoral artery at groin level. It requires frequent endovascular procedures owing to vein stenosis. Only 70% of all new created saphenous loop are functional with a 16-months survival rate [42].
\n\t\t\t\tThis AVG type is created at the groin using the common femoral artery as inflow, or at mid-thigh level using the superficial femoral artery instead [39,43]. Infection rate of thigh graft is higher than that of upper arm accesses.
\n\t\t\t\t\tA) Saphenofemoral arteriovenous fistula. (B) Arterioarterial HD through a superficialized femoral artery.
Ideally, mature AVF should have the following characteristics to be safely punctured: discernible vein margins, flow greater than 600 mL/min, vein diameter at least 0.6 cm and should be located no more than 0.6 cm deep [8]. Too deep lying arterialized cephalic veins, particularly in obese patients, can be superficialized either along its forearm course in case of RCF or along its upper arm course as in the case of BCF. (Figure 9). Since superficialization is an extensive, surgically complex and time-consuming procedure, we recommend to perform it as staged procedure on a case-by-case basis once the impossibility to cannulate the new access has been established. Superficialization of the vein can be done by surgical transposition [44], by single lipectomy [45] (or suction-assisted lipectomy [46]. Maturation time of BBF is about 8 weeks. Adequate puncture technique and care is the clue to prolonged VA survival. Cannulations can help to widen the caliber of the arterialized vein on condition that puncture sites are rotated. Lack of needle rotation may favor the development of aneurysms at neddling sites. However, some authors recommend the buttonhole cannulation and report less complications and interventions using this technique [47].
\n\t\t\tComplications in the immediate and early postoperative access complication are bleeding, thrombosis and infection. CKD patients are more prone to bleeding, but this complication is totally preventable with careful surgical technique. Significant bleeding associated with skin bulging at the operative site always requires surgical revision.
\n\t\t\t\tis the commonest complication of PVA in the immediate and early postoperative period. Even using an impeccable surgical technique and in the presence of both adequate vessel anatomy and optimal hemodynamic parameters, the risk of thrombosis remains high in the first minutes or hours after access surgery. Arterial wall incision done for anastomosis is in principle an arterial injury causing exposure of subendothelial elements as collagen and laminin which initiates a cascade of cytochemical and cellular events leading to platelet recruiting, adhesion and activation at the anastomosis site. Platelet activation together with thrombin generation results in thrombus formation [48]. In addition, chronic renal failure per se is a procoagulant state with multiple concurrent hemostatic abnormalities [49]. Some comorbidities like old age, obesity, diabetes, atrial fibrillation and hypertension could also contribute to enhance prothrombotic conditions. Therefore, close surveillance of fistula function, particularly in high risk patients, should begin just after unclamping of the vessels and continue after wound closure during the immediate and early postoperative period. Initially, a discontinuous sometimes high-pitched bruit may be heard over the anastomosis but in the following minutes or within the first hour it should turn into a continuous bruit which is the normal auscultatory finding in a well functioning fistula. In addition, fistula bruit must increase in intensity to a maximum in the first hours, remaining then stable. Decreasing fistula bruit, particularly during the first minutes or the first hour may herald impending thrombosis. Careful intravenous fluid and heparin administration may avert definite fistula thrombosis in a great majority of cases. In the event of complete bruit disappearance, a gentle massage can be done over the anastomosis area until the fistula bruit reappears. This massage can be repeated more than once if necessary [32]. Persistent discontinuous flow associated with pulsations instead of thrill over the outflow vein may point at an underlying outflow impairment.
\n\t\t\t\tin a new created VA needs aggressive therapy particularly because the anastomosis site is almost always involved and may rupture leading to acute, eventually life-threatening bleeding requiring urgent VA ligation. Infection is more common in AVG than in AVF [50]. Factors favoring infection are intraoperative contamination, poor wound care, diabetes, steroids, etc. Similarly as in NTC and TC, most episodes of infection are due to gram positive bacteria in particular, S. aureus. Infection at the anastomosis site may lead to fistula ligation or graft excision.
\n\t\t\t\tThrombosis in this period is most commonly due to hypotension after HD. The nursing staff should be strongly advised to always measure standing blood pressure (BP) before allowing a patient going back home after finishing HD session. If BP is found to be less than 110/70, the patient should be placed immediately in recumbent position until BP improvement. Tight circular bandages or dressings should be avoided. Since a new created AVF or AVG may cause a variable decrease in peripheral vascular resistance, antihypertensive drug dosing may eventually need to be adjusted. A bit higher median arterial pressure than usual (100-110 mmHg) should be tolerated in the first 10 days after surgery. Patients should be advised to keep their arm elevated to reduce local edema and decreased wound suture tension. Mild to moderate edema is not uncommon but it normally subsides within the first 3 weeks after surgery. In case of persistent or worsening edema, venous hypertension syndrome owing to an underlying central or peripheral vein occlusion should be suspected. Arterial steal is another complication that may also become clinically apparent during this period. Both the latter complications will be addressed in detail later in this chapter.
\n\t\t\tAs mentioned earlier a mature autogenous access requires
\n\t\t\t\tan adequate diameter (> 6 mm),
discernible margins,
adequate access flow rate (>500 ml/min) and
it must be sufficiently superficial (<0.6 cm deep) to permit accurate, safe cannulation.
Blood acces flow increases dramatically within 24 hours of autogenous access placement and reaches most of its maximum flow within 3 to 6 weeks [51,52]. Average flow rates vary according to access site and type. Mean forearm fistula fistula flow is 784 ± 623 ml/min, upper arm fistula 1400 ± 850 and prosthetic graft 1270 ± 604 [53]. Similarly, most of the increase in access diameter is achieved within 4 to 8 weeks of autogenous access placement [54]. It has been estimated that about one quarter to one third of AVF fail to mature [55]. Causes of lack of maturation are poor arterial inflow (inadequate vessel diameter, proximal atheroma, juxta-anastomotic occlusion of the proximal arterial limb, anastomosis of small size, chronic hypotension), juxta-anastomotic vein stenosis (probably resulting from intraoperative prolonged venous clamping), lack of ligation of tributary and collateral veins, venous intimal or media fibrosis not allowing vein diameter to enlarge. The usefulness of endovascular or surgical procedures to improve flow and promote AVF maturation should be evaluated in each particular case.
\n\t\t\tInfiltration are common complications. They may be confined to subcutaneous tissue looking like ecchymotic lesions or be the result of subaponeurotic bleeding, when the needle crosses the vein lumen leaving an orifice in the posterior vein wall [56]. In the latter case, skin bulging is seen without significant ecchymosis. Hematomas may eventually either become secondarily infected, cause significant stenosis or turn into pseudoaneurisms.
\n\t\t\t\tPA are typical puncture-related complications of both AVF and AVG. The trigger event is usually a wall laceration due to a traumatic cannulation with subsequent hematoma formation around the vessel or a leak at the anastomosis site leading to hematoma formation [57]. The size of the hematoma may vary widely and is one of the determinants of final PA size. Inadequate compression at puncture site favors further hematoma grow. PA may be located either subcutaneously or subfascially depending on where the hematoma was located. Once hematoma is formed around the fistula vein or graft, it will be progressively eroded in the course of few days by the pressure of a blood jet going out through the wall defect, which will later become the PA neck. Finally, a cavity or sac can be observed within the hematoma, connected to the fistula vein or graft lumen by the PA neck (Figure 12). PA can develop in both AVG and AVF. US guided compression of the PA for 30 minutes [58], or US guided direct thrombin injection into the PA sac have been used as primary options [59]. However, in case the latter measures fail or when PA is rapidly enlarging, revision is required. Surgical revision has been the standard approach to treat PA. However, endovascular treatment using covered stents insertion to exclude PA has been successfully used to treat such complications [57,60]. This method has proven safe and effective and the results has been encouraging, however it requires a specialized institution and the procedure-related costs are high. Surgery should be used in preference in case of wide-neck PA or when a significant skin bulge or mass is observed. Infection is a contraindication for endovascular procedures. In case of secondarily infected PA, the best way of action is to ligate the access in a definite manner.
\n\t\t\t\t\tA) Perigraft hematoma. (B) Doppler ultrasound show formation of pseudoaneurysm following hematoma cavitation.
Different than pseudoaneursyms, aneurysms are widened or enlarged segments of the arterialized vein that may develop at puncture site or at the anastomosis. Aneurysms may reach significant sizes and exhibit small saccular areas with thin wall which may cause, if ruptured, serious bleeding, Aneurysms usually limit puncture sites and can be the starting point of infections and thrombus formation. In selected cases, surgical plication may be attempted to reduce aneurysm size on condition that a proximal stenosis of the vein is excluded [61]. Otherwise, ligation of the access is the only option.
\n\t\t\t\tInfection can develop at puncture sites, poor aseepsia, hematoma formation or infiltrations being predisponent factors. Most commonly isolated agents are grampositive bacteria, particularly S. aureus and coagulase-negative staphylococci [62]. AVF or AVG infection should be always viewed as an emergency condition that require hospitalization since it may ultimately lead to access rupture with bleeding, sepsis, endocarditis and other metastatic infections. Aggressive empirical antibiotic therapy should be started until culture results are available. Strict adherence to aseptic and antiseptic protocols by the nursing staff and patient’s education are instrumental in preventing access-related infections.
\n\t\t\t\tLuminal stenosis may range from mild to severe and can develop at any site along the AVF or graft (anastomotic stenosis, peri or postanastomotic stenosis, puncture-related stenosis, stenosis at the site of former venipunctures and venous outflow stenosis). While anastomotic or puncture-related stenosis point at surgical failure or inadequate puncture technique, perianastomotic stenosis in AVF and venous outflow stenosis at the graft-vein anastomosis are due primarily to neointimal hyperplasia [63]. Other possible causes of postanastomotic stenosis might be venous wall damage induced by clamping and excessive denudation of the vein. The diagnosis of luminal vein stenosis can be accurately done in a great majority of arteriovenous fistulas by physical examination alone [64]. CDU or other vascular imaging techniques should be used to confirm the clinical diagnosis of stenosis. Treatment of stenosis is either surgical or endovascular (balloon dilatation or stent placement) and the results depend largely on the size and type of the stenosis. The KDOQI Guidelines [7] recommend that stenoses in prosthetic or autogenous accesses should be treated prophylactically with percutaneous transluminal angioplasty or surgical revision if the stenosis is 50% of the lumen diameter and is associated with clinical abnormalities. Early detection of fistula vein stenosis can be achieved by applying the KDOQI static intra-access pressure surveillance protocol which consists of serial calculations of the normalized arterial and venous segment static intra-access pressure ratios or indexes. Arterial index values > 0.43 in AVF or > 0.75 in AVG are suggestive of significant stenosis [65]. Index calculations and normal range values are described in detail in the respective KDOQI recommendation [7].
\n\t\t\t\tof the runoff vein is a special type of stenosis which has been subject of extensive research. Cumulative patency of AVG largely depends on the development of neointimal hyperplasia at the graft/venous anastomosis. Therefore, prevention of this complication would contribute to prolong AVG survival [63]. Research has been focused on how to eliminate or inhibit the two main pathogenetic factors involved in the development of this complication: Shear stress and the subsequent endothelial cell proliferation. Shear stress has long been pointed as the main cause of neointimal proliferation as proved in experimental flow models. Some modifications in graft configuration have been shown to reduce shear stress, particularly on the bed of graft-vein junction, like helical ePTFE grafts which swirl blood flow across the graft-venous anastomosis reducing endothelial stress [66]. Another way to limit neointimal hyperplasia is reducing venous outflow turbulence either by modifying the graft-vein anastomotic angle inserting grafts with angled \nvenous end [67] or with the so called Y-Split AVG (Prolong™) that bifurcates shortly after arterial end and reunite just before the runoff vein anastomosis [68]. Inhibition of endothelial cell proliferation has been achieved on the one side by embedding allogeneic aortic endothelial cells in a gelatin matrix (Vascugel™), which is placed around the vessel at the time of AV access creation. Preliminary studies have been promising but further research is needed [69]. On the other side, it has been long known that increased nitric oxide levels inhibit the intimal hyperplasia of grafts [70]. In this regard, worth-mentioning is the interesting work by Luo et al [71] who evaluated the efficacy and safety of an adenoviral vector encoding the carboxyl terminus of beta-adrenergic receptor kinase in a pig model of arteriovenous PTFE graft failure. The authors found that locally applied gene therapy reduced significantly neointimal hyperplasia in the graft/vein anastomosis.
\n\t\t\t\tAccess recirculation occurs when dialized blood having already passed through the dialyzer, instead of returning to circulation via the proximal “venous” needle, is redirected toward the distally placed arterial needle and reenters the extracorporeal circuit. The explanation is that flow of the extracorporeal circuit exceeds that of the VA whose minimal range should be between 300 to 450 mL/min [72]. Recirculation results in dialysis delivery being less than that prescribed. The most common cause is stenosis of the outflow vein which can ultimately lead to access thrombosis owing to significant intraaccess flow reduction. Other causes to be excluded are poor arterial inflow, close proximity of the needles and inverted lines. Complementary imaging methods like Doppler ultrasound, venography, angioresonance, etc, can locate site and determine degree and extension of the stenotic segment, measuring access recirculation is a valuable tool to estimate the percentage of recirculation and help to establish the indication for surgical or endovascular interventions. Recirculation may be measured either by urea-based or non-urea based methods like ultrasound dilution, potassium dilution, ionic dialysance, glucose infusion and thermal dilution [73]. Percentage recirculation can be calculated by the traditional urea-based method according to the following equation: [Systemic BUN-arterial blood line BUN/Systemic BUN-venous blood line BUN] x 100. Consistency of the urea-based methods is poor for surveillance for access stenosis, in part because of arteriovenous (cardiopulmonary recirculation) and venovenous disequilibrium [74,75] but if the percentage recirculation is >10% stenosis should be suspected. Other methods which eliminate the effect of disequilibrium have different thresholds, such as > 5% for ultrasound dilution [76].
\n\t\t\t\tAlso referred to as HD access-induced distal ischaemia (HAIDI), ASS is a rather uncommon complication and occurs in 2.7–4.3% of AVG and 1% of AVF [77,78]. It may appear early after surgery or in the postcannulation period. Symptoms range from only pain and coldness during dialysis to digital necrosis. It may develop shortly after surgery or years afterwards. Patients at risk are diabetic and those with severe peripheral occlusive disease. ASS may be classified in 4 stages [79]:
\n\t\t\t\t\tStage 1: Retrograde diastolic flow without complaints; steal phenomenon;
Stage 2: Pain on exertion and/or during HD;
Stage 3: Rest pain and
Stage 4: Ulceration/necrosis/gangrene.
The diagnosis of steal syndrome is made clinically, color Doppler US and complementary imaging procedures. Measuring finger pressure before and after fistula vein or graft compression is a very helpful diagnostic manoever in patients with steal syndrome. Using the digital brachial index (DBI), Goff et al [80] identified patients with a DBI of <0.45 as having a significant risk for ASS. Treatment of ASS is surgical and has two main objectives: increasing or restoring distal limb flow and maintaining access patent. Surgical interventions to obtain symptoms relief in SS are of two kinds:
\n\t\t\t\t\tRevascularization and
Banding.
The more severe forms require excision or removal of the affected tissue.
\n\t\t\t\t\tA) Steal syndrome with painful necrotic ulceration of the middle finger. (B) Stage 4 steal syndrome.
Distal revascularization with interval ligation (DRIL) was first described by Shanzer et al [81] as early as 1988 and consists in placing an arterioarterial bridge that bypasses the anastomosis site. In addition, a juxta anastomotic ligation of the distal limb of the artery is done. It has been long viewed as the gold standard procedure.
Proximalization of the arterial inflow: First, the distal original arteriovenous anastomosis is closed and the artery repaired using an interposition graft. Secondly, the outflow vein is anastomosed to a bridge graft (autologous or else) which is in turn anastomosed to a more proximal site of the artery. This procedure is useful in cases with low fistula flow [82].
Revision Using Distal Inflow (RUDI). In this technique the original anastomosis at the brachial artery is ligated and the outflow vein is anastomosed more distally to either the radial or ulnar artery just below the bifurcation using a bridge graft (autologous or ePTFE). The basic principle is that the distal artery has both lower diameter and flow [83].
The main objective of banding is to increase postanastomotic outflow resistance by narrowing the lumen of the outflow vein or graft so as to reduce outflow and increase distal arterial flow. Banding may be achieved either by placing a narrowing suture near the anastomosis site [84], by plication of a short postanastomotic stretch [85] or by tapering [86]. Flow reduction in either technique is measured by means of intraoperative pulse volume recording or by measuring access flow with a flow meter [87]. Among the banding techniques, the minimally invasive limited ligation endoluminal-assisted revision (MILLER) for treatment of dialysis access-associated ASS is one of the most simplest to perform and offers excellent results [88]. In this technique one or two sutures are placed 1-3 cm after the anastomosis using an inflated endoluminal angioplasty balloon, which is retrogradely inserted more proximally, to size the final luminal diameter of the outflow vein.
\n\t\t\t\t\tIt is a rather uncommon complication which can easily be overseen [89]. Excessive shunting of the access, anemia and underlying heart disease are triggering factors. Surgical banding [90] may relieve symptoms, but in case of persistent manifestations, definite ligation is the only remaning option.
\n\t\t\t\tVHS is a relatively common complication of AV accesses, particularly AVF and consists of a painful edema, redness and warmth of the affected skin area that appear after VA creation that may affect, depending on the site of the outflow stenosis or occlusion, either the entire upper extremity or may be circumscribed to forearm, hand, or skin segments overlying the fistula. The stenotic site represents a formidable barrier against arteriovenous flow originating a steady rise of the intraluminal pressure distally to the stenosis. The increased intraluminal pressure is in turn transmitted backward to the superficial or subcutaneous vein system producing the typical symptoms of VHS (Figure 14). In patients with longstanding VHS skin pigmentation occurs as well as other manifestations observed in chronic venous insufficiency like vein collaterals, small varicosities and even ulcerative lesions. The mechanism of hyperpigmentation is possibly similar to that of chronic venous insufficiency where both a moderate hypermelanosis and dermal hemosiderin deposits can be seen microscopically, derived from the breakdown of red blood cells that have extravasated through damaged capillaries and smaller vessels are [91]. Diagnosis of VHS is made clinically and should be complemented by imaging procedures like ultrasound, flebography, angiotomography or angioresonance. The main advantage of the two latter procedures is that small dosis of contrast media are used. Treatment options are: Ligation of retrograde veins, endovascular or surgical procedures or definite access ligation.
\n\t\t\t\tThe purpose is to perform an arterioarterial hemodialysis. The arteries reported to be used this way are: the superficial femoral [91], the brachial [92] and radial artery [93].
\n\t\t\tDesperate case access option that has been performed as axillary-axillary chest loop (preferred type) or femorofemoral loop. Reported primary and secondary patency at 3 years were 54% and 87%, respectively [94].
\n\t\t\tThese are a particular type of VA. The axillary artery is anastomosed by means of an ePTFE graft to either the ipsitaleral axillary vein, internal jugular or femoral vein. Loop configuration of the graft at the upper chest is the typical configuration when either the axillary or the ipsilateral internal jugular vein is used [95]. If the contralateral axillary vein is used as outflow, ePTFE configuration in the form of a collar or necklace is placed. Mickley et al [96] described a novel AVG using the axillary artery as inflow and the right atrium as outflow in cases with superior vena cava occlusion.
\n\t\t\t\tA) Venous hypertension syndrome developing after a brachiocephalic fistula creation (B) Angiotomography showing right innominate vein occlusion.
Xenografts are more expensive than PTFE grafts, a fact which limits their use in spite of their proven better patency rates and lesser frequency of complications compared to PTFE graft [97-99]. Two types xenografs are commercially available:
\n\t\t\t\tThe bioingeneered bovine carotid artery (Artegraft™) which has been in use since 1970 and
the bioengineered bovine mesenteric vein (Procol™).
The Hemoaccess Reliable Outflow (HeRO™) Vascular Access Device (Hemosphere, Inc., Minneapolis, MN) has emerged as a valuable, innovative alternative to tunneled catheters (TC). Early results suggests that bacteremia was significantly less frequent for the HeRO device than for TC being its secondary patency (> 72.2%) quite close to that of PTFE grafts [100-102]. According to the description by Katzman et al [102], this device consists of a 6-mm straight ePTFE upper arm graft serving as cannulation segment, whose distal end is anastomosed to the brachial artery and the proximal one is attached by means of a titanium-made crimp ring to an also subcutaneously placed, 5 mm inner diameter, silicon catheter ( “outflow component”). The catheter may be introduced endovascularly or inserted into the internal jugular or subclavian vein utilizing the Seldinger technique The catheter tip should lie at the cavoatrial junction.
\n\t\t\tTheir main advantage is that they can be used 24 hours after placement and would avoid using NTC and TC preventing catheter-related morbidity and costs. Some of the ESG have resulted from modifications introduced to the original ePTFE like the Trilaminate composite construction ePTFE (Flixene™) which would have reduced hole bleeding, being ideal for early use [103] or the gelatin-coated ePTFE (Vascutek™). The gelatin would make subcutaneous graft placement smoothly preventing tissue trauma and thus allowing early graft cannulation. However, with the latter a high incidence of perigraft hygroma has recently been reported [104]. Other ESG are made of polyurethane urea (Vectra™) which is an antithrombogenic material with an impermeable middle layer. The graft would seal rapidly after decanulation being thus ideal for early use [105,106]. A really innovative development as graft material in the future is the endothelialized polyurethane grafts (NanoVasc™) which has a biomimetic scaffold allowing for endothelial cell ingrowth. The results of animal studies are encouraging [107].
\n\t\t\tThe creation of AVG using TEVG technology is really very promising. Some are created by seeding autologous bone marrow-derived mononuclear cells onto biodegradable tubular scaffolds constructed mainly from derivatives of the extracellular matrix or using allogeneic or canine smooth muscle cells grown on a tubular polyglycolic acid [108]. Other TEVG grafts are created from autologous fibroblasts and endothelial cells obtained from small skin and vein biopsies. The grafts are implanted without synthetic scaffolding [108].
\n\t\t\tAs stated in the introduction paragraph, during the past two decades, HD population has become increasingly composed of patients of advanced age and/or suffering from comordibities like diabetes, hypertension, chronic hypotension, dyslipidemias, occlusive artery peripheral disease, malnutrition, etc. In this population the risk of VA loss or malfunction is extremely high, particularly when two or more comorbid conditions coexist.
\n\t\t\tare prone to complications like occlusive arterial disease which limits their access options and, in a significant proportion of them, the primary access has to be created at upper arm due to severe atheromatous changes of distal arteries. The risk for development of arterial steal syndrome in patients of this group is elevated. In addition, a subset of diabetic patients suffer from chronic hypotension, orthostatic hypotension, etc., owing to autonomic neuropathy or cardiac failure. Access thrombosis is very common among those patients and, in many of them, a TC for chronic HD or CAPD are often the only remaining option.
\n\t\t\tdefined as interdialytic systolic pressure of less than 100 mmHg without cardiac function impairment, affects 5 to 10% of HD population. Its pathophysiology is not well understood but the mechanism of hypotension seems to be a reduction of the peripheral resistances with poor response to midodrine and other vassopresor agents [109]. In these patients frequent VA thrombosis are observed. The creation of upper arm fistulas has been recommend as primary access choice in such cases [110].
\n\t\t\thave been associated with AV access thrombosis [111]. In addition, serum albumin is a known marker of nutritional status in HD patients. Hypoalbuminamia is associated with malnutrition and the latter, in turn, may lead to poor wound healing, infection and subsequent VA loss [112]. Hyperhomocysteinemia has also been found by some authors to be a risk factor for VA thrombosis and suggest decreasing levels before performing any VA [113]. Others, on the contrary, found no association between risk for thrombosis and hyperhomocysteinemia [114]. Further studies are necessary to clarify whether lowering plasma homocysteine concentrations may prevent VA failure in HD patients.
\n\t\t\tPatients with SLE on HD are at increased risk of vascular access thrombosis as compared to non-SLE patients because of the high prevalence of the so called, antiphospholipid antibodies, namely, anticardiolipin antibodies and lupus anticoagulant among SLE patients. [115 - 117]. Lupus anticoagulant is actually a prothrombotic agent which precipitates the formation of thrombi in vivo. In addition, SLE patients on chronic HD receiving high dosis of oral steroids, may have an elevated risk of VA thrombosis and infection and, for this reason, steroid dosis should be reduced before performing VA surgery.
\n\t\t\tThe ideal AVG, which can be created with graft materials similar to the patient’s own vessels is yet to be invented. However, a lot of progress has been done. The best example is TEVG technology which are showing us a complete new world in the realm of HD accesses in the future. Likewise, early stick grafts are undoubtedly unvaluable developments which have raised special attention because they could obviate the need for a bridging NTC or TC. However, before resorting to all that panoply of innovative developments whose extensive use would otherwise represent a serious financial burden for any health care system, there is a lot that can still be done. Catheters have been a necessary evil but one step in the right direction is avoiding or minimizing their use in the years to come. To reach this goal, increasing pre-dialysis construction of autogenous fistulas is the only way out of the current trend. Applying autogenic-oriented VA plans is another crucial step that could help to substantially decrease the use of grafts. Additionally, but equally essential measures are complications prevention through patients’ education, continuous staff training and timely-performed VA preserving interventions. Certainly, we will continue finding patients with very difficult access who will benefit from all those innovative AV types described in this chapter. Yet, it would not be far from the truth to state that the VA needs of the overwhelming majority of our patients could be met with a simple autogenous fistula if timely done, adequately punctured and optimally cared.
\n\t\tThe author thanks NOVARTIS-NOVACID, Caracas, Venezuela, for their unvaluable bibliographic support.
Global agriculture is facing the difficult challenge of increasing the productivity and output required to feed a growing population. Additionally, fertile land areas available for agriculture are gradually decreasing due to climate change, soil degradation, and pressure from urban developments. These concerns are particularly relevant as they negatively affect yields of cereal crops, which are a fundamental diet component in global society [1].
\nTo help overcome this problem, researchers have turned their attention to understanding interactions between plants and soil microorganisms. Plant roots interact with the soil microbiota, which have various effects on plant growth and development, ranging from beneficial to pathogenic [2]. Plant growth-promoting rhizobacteria (PGPR) play important, but still poorly understood, roles in plant growth promotion, especially under environmental stress such as drought, temperature, and salinity [2, 3, 4].
\nThere are various mechanisms through which PGPR improve plant performance, often in a synergic manner; some examples include the production of plant growth-promoting hormones, improvement of plant nutritional status, and decreased stress damage [2]. Interactions between plants and PGPR can result in improvement of plant performance and enhanced resistance to biotic and abiotic stresses which are important traits for cultivated crops [5].
\nCereals are annual plants belonging to the monocotyledonous Poaceae family and are a vital food source for humans as they provide almost one half of the calories that are consumed daily in the world [6]. Furthermore, cereals are also extensively used as animal feed, mainly for livestock and poultry, and as raw materials for many industrial processes, primarily the production of alcoholic beverages [1].
\nIn the last 50 years, the increase of cereal production (+240% in the time window 1961–2017 shown in Figure 1) is the result of increased yields per hectare (+201%) rather than the expansion of land allocated to cereal production (+12%) (Figure 1). However, this trend has recently decreased. The average production rate of cereals was 3.6% per year between 1961 and 2007, and it decreased to an average of 2.7% between 2007 and 2017 [7]. This is likely to be linked to multiple factors, including climate change, soil degradation, use of soil for non-alimentary purposes, restrictions on water, nutrients and land for agriculture, and limitations of traditional breeding.
\nCereal cultivation records and world population data since 1961. Cereals cultivated land, soil productivity as yield, world grain production, and world population are displayed [7].
Most cultivated soils in the world are characterized as being suboptimal. Any deviation from optimal growth conditions causes several interconnected reactions in plants that can be described as an attempt to adapt to new environmental conditions in an effort to maintain homeostasis. If the stress endures too long or is too severe, it can permanently damage plant physiology or result in death. While many plants are able to adapt to stress, the process requires energy that is diverted from active growth, resulting in smaller acclimated plants [8]. Abiotic stresses, that is, stresses caused by nonliving factors, are thought to be the main cause of global crop loss with decreased productivity of more than 50% annually [9]. Drought and salinity stress are potent environmental hazards for agriculture, particularly in arid and semiarid regions which are already approaching the limits of crop productivity, and due to global warming and degradation of agricultural soils, these regions may no longer support crop plants in the future [10, 11].
\nFood security is positively correlated with social and economic stability; given climate change is threatening food production, there are extended and complex implications. Since the mid-nineteenth century, average temperatures have increased by 0.8°C, and by the end of this century, temperatures are predicted to increase between 1.8 and 4°C compared to the end of the last century [12]. This change is causally related with human activities by the production of greenhouse gases such as carbon dioxide, the concentration of which rose from ~284 ppm in 1832 to 397 ppm in 2013 [13].
\nWhile CO2 is generally accepted as a greenhouse gas, there is now increased interest in the role of nitrous oxide (N2O). This compound can originate from the denitrification of N fertilizers, which are commonly used in modern agriculture. In 2014–2015, more than half of all N fertilizer was applied to cereal crops alone [14]. The reintroduction of N in N-depleted soil is an essential agricultural practice that has led to increased yields over the last few decades. However, the application of N fertilizer is inefficient, and it is estimated that only one third of the applied N is absorbed by plants, with the excess being lost in surface runoff, leaching in groundwater, or volatilization into the atmosphere [15]. Atmospheric N2O, while less abundant than CO2, is 300 times more potent as a greenhouse gas [16].
\nClimate change caused by greenhouse gas emissions is predicted to directly impact the productivity of agricultural systems in almost every part of the planet. While many agricultural sites in cold-continental areas will benefit from the increased temperatures, regions characterized by temperate, tropical arid, or subarid climates are likely to face decreasing yields [17]. By modeling the effects of climate change on the yields of various cereals in different areas of the world, it was predicted that by the end of the century, heat stress events will increase in areas of Central and Eastern Asia, Southern Australia, Central North America, and Southeast Brazil (rice); Northern India, the Sahel region, Southeast Africa, and Central South America (maize); and Central Asia (wheat) [18]. Kompas et al. [10] estimated that if no measures are taken to reduce greenhouse gas emissions, the average world temperature increase of 4°C by 2100 will severely decrease food production in almost all countries in the world. This will result in economic loss of approximately 23 thousand billion US$ on average, with Southeast Asia and developing countries of Africa predicted to face the largest losses (21 and 26% of GDP, respectively).
\nSoil degradation is one of the main concerns impacting agricultural productivity, especially in tropical and subtropical areas [19]. Globally, one third of land is affected by some form of deterioration [20]. Unsuitable agricultural techniques, together with excessive crop residue removal and unbalanced use of chemical fertilizers, can decrease soil quality, deplete organic matter stocks, and increase erosion. Crop removal from the production site causes the loss of elements that are essential for plant growth, and these elements must be constantly reintroduced to avoid productivity decreases [21].
\nUsing soils for agricultural purposes can cause degradation of water sources, due to leaching of degraded fertilizers into groundwater. Many rivers in developing countries have severe water pollution and eutrophication issues. Irrigation is an essential management strategy to obtain sufficient productivity to meet food demands in many arid and semiarid areas, but it can lead to undesirable effects. Improper irrigation techniques have increased saline-sodic soils that now occur in more than 20% of irrigated lands [22].
\nA common misconception during the nineteenth century was that healthy plants should be sterile, not interacting with any microorganisms. This assumption was initially questioned by Victor Galippe [23], who proved that healthy plants could host various microbes in their tissues. Today, we know that almost all terrestrial plants from various environments interact with the surrounding microbiota during all stages of plant development. The relationship between host plant and microbe can range from parasitism, commensalism or mutualism, or neutral or beneficial for plant growth and can vary greatly due to a multitude of factors, both biotic and abiotic. PGPR are attracted to plants by organic exudates released through roots and colonize the root surface and the soil directly in contact with the root. The soil matrix directly in contact with plant roots is called the rhizosphere [24], and the extracellular surface of roots is termed the rhizoplane [25]. Here, colonizing microorganisms can establish the exchange of nutrients and various compounds with the plant, summarized in Figure 2.
\nA model of interactions between plants and PGPR. Exudates released by plant roots attract soil bacteria that can colonize rhizosphere and/or plant tissues. Here, they provide various beneficial compounds to the plant in exchange of nutrients, mainly photosynthates.
Nutrients and organic compounds released into the rhizosphere from roots are derived from photosynthesis, and plants release up to 30% of their photosynthates through the roots [26]. These include a variety of compound classes such as carbohydrates, amino acids, organic acids, flavonoids, and lipids that can be used as energy sources for microbes [27]. The sensing and active migration of bulk soil bacteria toward these compounds is called chemotaxis, leading bacteria to colonize the rhizosphere and rhizoplane [28]. By producing exudates, plants can select bacterial species that are attracted to specific compounds, thereby directing the abundance and diversity of microbes in the rhizosphere [29, 30]. Wild oat has been reported to modify the bacterial population of its rhizosphere enriching mainly the Firmicutes, Actinobacteria, and Proteobacteria [31]. The latter group in particular is commonly believed to be the main microbial component in PGPR interactions, due to their capacity for fast growth and diverse metabolic pathways capable of utilizing a great variety of exudate compounds as an energy source [29]. In the model cereal plant Brachypodium, the rhizosphere microbiome changes not only within the loosely bound rhizosphere soil and tightly bound rhizosphere soil but also within seminal and nodal roots [32]. It is noteworthy that plants can indirectly influence the colonization of the rhizosphere, by changing the environment conditions. Some examples are changes in pH levels by ion uptake, the reduction of O2 and H2O levels caused by root respiration, and water absorption [29].
\nDifferent types of root exudates can attract different PGPR. For example, various strains of Azospirillum brasilense, a gram-negative Alphaproteobacteria, showed different degree of attractions to various compounds released by different host plants [33]. The composition of root exudates can vary greatly among different plant species. Two different studies [34, 35] reported how even different genotypes of the same plant species can host different bacterial populations in their rhizosphere. Exudates vary between different parts of the roots, different developmental stages of the plant, or as a response to different growth conditions [36]. This means that the same plant can interact with a multitude of different soil bacterial strains over time and space [37].
\nNehl et al [38] use the term “rhizobacteria” to describe rhizoplane/rhizosphere bacteria, but there are also endophytic bacteria that can reside inside plant tissues. To date, numerous interactions between plants and rhizosphere-/rhizoplane-colonizing bacteria have been described, but some microbes are even more specialized. Once they have colonized the rhizoplane, they are able to penetrate root tissues and directly access apoplastic organic compounds, thereby avoiding competition with other microbes in the rhizosphere [39]. Root penetration can be both active, by the production of cell wall-degrading enzymes such as cellulase, and passive, for example, entering via the cracks that form on the root surface during lateral root development [40]. Colonization beyond the rhizosphere into the apoplast requires specialized microbial morphology. Czaban et al. [41] described how the occurrence of flagellar motility in bacterial strains isolated from the internal root tissue of wheat was five times higher than what was observed in bacteria isolated from the rhizosphere.
\nBacillus, Pseudomonas, Enterobacter, Klebsiella, Serratia, and Streptomyces are some of the most commonly found genera of endophytic bacteria in plant tissues [42]. By passing the endodermis, many bacterial species are able to spread from the roots, reaching and colonizing other organs of the stems [43]. Endophytic bacteria can also spread from plant tissue to seeds becoming the starting inoculum for the colonization of subsequent generations of plants. The transmission of bacteria through generations of plants is a process known as vertical transmission. Johnston-Monje and Raizada [44] described how modern varieties of maize and their wild ancestors share common endophytic bacteria communities hosted in their seeds, and a following study conducted on wheat demonstrated how these communities play a positive role in plant growth [45].
\nGalippe’s intuition that plants interact with microbes throughout their life led to a significant increase in the comprehension of the beneficial role that bacteria can have on plant growth. PGPR interactions can result in higher plant biomass, higher nutritional value, better survival rates, and generally require lower agricultural inputs. Focusing on cereals, PGPR can significantly improve plant performance in several environments, particularly those characterized by suboptimal growth conditions. Some of the main benefits that plants obtain are increased root development which imparts improved resistance to temperature and osmotic stress, soil pollutants, pests, and pathogens [46].
\nIt is well established that plant responses to biotic and abiotic stresses require complex adaptations to structure and metabolism. When biotic and abiotic stresses are applied simultaneously, plants respond much differently compared to stresses applied separately [9]. It is therefore reasonable to assume if a plant is exposed to both biotic and abiotic stresses that PGPR may directly mitigate the effect of biotic stresses by improving plant resistance to abiotic stresses.
\nThe most well-described mechanism by which PGPR can improve cereal productivity is the productions of various plant growth-promoting hormones that usually co-affect the performance of the plant in a highly integrated manner [47]. Auxins are a class of hormones typically synthesized by apical buds, and from there they are transported to other parts of the plant. In this class of hormones, the most characterized is indole-3-acetic acid (IAA), which enhances cell elongation and differentiation and, in roots, stimulates lateral root development [42, 48]. Various reports have shown how the production of auxins from PGPR is one of the most important mechanisms for plant growth promotion. Barbieri and Galli [49] inoculated wheat with two strains of Azospirillum brasilense, of which one was a mutant with impaired IAA production. They observed how only the wild-type strain promoted lateral root development, a result that suggests a primary role of IAA in improving plant root development. IAA can indirectly improve the nutritional status of the plant by increasing root development (specifically lateral roots), hence allowing the plant to explore a higher portion of soil substrate, an important trait particular for the acquisition of low-mobility nutrients such as phosphorus [50].
\nGibberellins (GAs) can be produced by PGPR [51] and are believed to play an important role in promoting plant growth. These diterpene hormones are naturally present in plants, regulating key processes such as seed germination, stem elongation, leaf expansion, root growth, and root hair abundance [52, 53]. One of the best known GAs is GA3, commonly known as gibberellic acid, which plays a key role in determining plant source-sink relations. The role of gibberellins in the response of cereals to stresses varies depending on the stress type [54], but in general, plants tend to reduce GAs levels when growing in suboptimal conditions. The exogenous application of gibberellins has been reported to improve wheat and rice performance undergoing saline stress [55, 56] and to reduce heavy metal stress symptoms in rice [57].
\nMany PGPR are able to degrade 1-aminocyclopropane-1-carboxylic acid (ACC) through the enzyme ACC deaminase and use the degradation products as a nitrogen source [42]. ACC is the biosynthetic precursor of ethylene, a hormone naturally present in plants, and its abundance is often increased in response to stresses. While at optimal levels, ethylene is involved in essential processes such as tissue differentiation, root development, flowering, grain development, and natural tissue senescence and abscission; when overproduced it can decrease plant performance [58]. In abiotically stressed plants, the increase of ethylene can trigger chlorosis and early maturation and senescence of organs, seeds in particular [59, 60], and have an inhibitory effect on root growth [42]. By impairing the ethylene signaling pathway, the interaction with PGPR can decrease the stress-related damage in the plant [2].
\nSimilar to ethylene, abscisic acid (ABA) is a hormone commonly produced by plants in response to various types of stress, particularly osmotic stress [61]. Naturally involved in seeds and buds dormancy, ABA shares the first biosynthetic steps with cytokinins, a phytohormone class that often plays an antagonistic role to ABA. In dry or saline soils, reactive oxygen species (ROS) increase the biosynthesis of ABA, which is then transported to leaves, where it causes stomatal closure to reduce transpiration and water loss [62]. As a consequence, the diffusion of CO2 into leaves is decreased, lowering photosynthetic rates [63, 64]. PGPR have been reported to increase the resistance of plants to salinity, hence decreasing the stress-related ABA accumulation in plants and preserving photosynthetic efficiency [65, 66].
\nBacteria can have various effects on their host plant. PGPR can affect plant growth both directly, such as by fixing atmospheric N2 into biologically available N compounds or by producing growth-promoting hormones [52], and indirectly, by preventing the growth of plant pathogens or increasing plant resistance to them [43]. A necessary condition for bacteria to be beneficial to a plant is rhizosphere competence as the competition and conditions in the rhizosphere are vastly different to that of bulk soil. The rhizosphere contains a higher abundance of bacteria than bulk soil, but the diversity is much lower. The colonization of the root system of plants is not homogenous; the density of specific bacteria varies in different parts of the root system and is likely to be related to different root exudates released by different parts of the roots [37]. Another mechanism likely to regulate the colonization of the rhizosphere is bacterial quorum sensing, which is the regulation of gene expression driven by bacterial population density and can occur both within bacteria of the same species and among different species [67]. Quorum sensing can influence the bacterial competitiveness, therefore affecting the roots colonization patterns [37].
\nTemperature stress causes a shift in hormone production, particularly ethylene, which can often impair plant growth [58]. High-temperature stress causes denaturation and aggregation of cellular proteins that, if left unchecked, leads to cell necrosis. Imbalance between ABA and cytokinins derived from prolonged heat stress during the reproductive stage can lead to grain abortion [68]. Heat responses include inhibition of normal transcription and translation and increased expression of genes coding for heat shock proteins and thermotolerance induction [69]. Low-temperature stress, conversely, damages metabolic processes, changes membrane properties, causes structural changes in proteins, and inhibits enzymatic reactions [70]. If it occurs during spore formation, cold can cause sterility of flowers by interfering with meiosis [71].
\nThe literature on PGPR interactions with cereals at suboptimal temperatures is relatively scarce, and the mechanisms by which cereals adapt are not well defined. It is suggested that the geographical origin of the bacteria determines the optimal growth range at which they interact beneficially with plants. In a study on wheat, bacteria isolated from cold climates have been reported to efficiently colonize the plant rhizosphere and improve their resistance to low-temperature stress, and the same trend was observed when wheat plants were inoculated with bacteria isolated from warm environments and subjected to high-temperature stress [72]. It is possible that the bacteria isolated from different temperatures can outcompete the indigenous microbial population by tolerating either cold or warm conditions giving rise to a higher abundance and colonization of the rhizosphere.
\nInoculation with a Pseudomonas aeruginosa strain isolated from a hot semiarid environment improved survival rate, development, and biochemical parameters of sorghum seedlings when the plants were exposed to heat treatment, while the biomass production was not affected at optimal temperatures [73]. In another study, various cold-tolerating Pseudomonas spp. were inoculated onto wheat grown at low temperatures, giving analogous results. The authors suggest the beneficial effect was linked to a better root development in inoculated strains that improved nutrient uptake and, in general, caused a better adaptation to cold [74].
\nAs global warming threatens to change significantly the temperature of most cultivated lands [17], the development of cereals with enhanced adaptation capacity to heat or cold stress is an essential task in order to sustain profitability and production at suboptimal temperature conditions. While further research is necessary to better understand the mechanisms that regulate PGPR-plant interactions in such conditions, the studies done so far suggest how PGPR can be a valuable source of temperature-stress resistance, especially when they evolved in areas characterized by warm or cold climates, depending on the case.
\nBoth dry and saline soils can cause osmotic stress in plants, which results in cell dehydration due to lack of water (drought) or unavailability of water (salinity). These two stresses are often agronomically significant, as high salinity in soil is mainly caused by irrigation, a necessary practice for increasing yields in many areas of the world characterized by insufficient rainfalls. When water supply is insufficient to remove ions from superficial soil layer, they accumulate causing an increase of salinity [75].
\nSalinity is also the result of land clearing, as deep subsurface roots no longer are able to keep the water table below ground level. As the water table rises, it brings with it saline water that can render hundreds of square kilometers of agricultural land uncultivable [76]. Plants growing on such soils often suffer from osmotic stress that reduces water absorption and increases ionic concentration in tissues to toxic levels [77]. PGPR can decrease these stress symptoms through various mechanisms, such as production of Na+-binding exopolysaccharides [78], improvement of ion homeostasis [79], decrease of ethylene levels in plants through ACC deaminase [80], and synthesis of IAA [81]. Wheat seeds inoculated with a species from the genus Pseudomonas showed increased germination rates in a saline environment; Egamberdiyeva [82] ascribed this to the production of plant growth regulators by the bacteria.
\nDrought is considered as the major cause of yield loss [83], negatively affecting most physiological processes in plants. Plant cells respond to water loss by increasing the production of abscisic acid (ABA) in roots that increases water uptake and causes leaf stomatal closure and reduces leaf expansion to reduce dehydration [84]. Smaller leaves cause impaired photosynthesis, consequently decreasing dry matter accumulation and grain yield [85]. Under water deficiency, both cell division and enlargement are lowered due to damaged enzyme activities, leading to overall smaller plant organs. Grain production is also reduced in cereals due to flower abortion [86, 87].
\nPlants often react to drought by increasing the amount of osmolytes in their tissues and consequently increase their osmotic potential [88]. Drought can also cause an increase of ROS in plant tissues. Proline, an amino acid whose abundance is increased under water deficiency, can both work as an osmolyte and scavenger for ROS under stress [89]. In general, PGPR can improve the performance of plants in dry environments by exudating osmolytes that increase the osmotic potential of plants [42, 90, 91].
\nAnother mechanism for improving resistance to drought is the synthesis of beneficial hormones (IAA) and enzymes (ACC deaminases) and the decrease of stress-related hormones such as ethylene and ABA in the plant. Naveed et al. [92] reported that two maize cultivars exposed to drought showed reduced damage when inoculated with two different PGPR, probably due to hormones produced by the bacteria and stress-reducing enzymes synthesized by both the plants and the bacteria during the interaction. Wheat plants inoculated with various PGPR showed an improved resistance to salt and drought treatments, linked to decreased ABA and ACC levels in plant tissues [65]. In a similar study [66], rice plants showed decreased endogenous ABA levels and increased biomass when inoculated with Bacillus amyloliquefaciens; the authors hypothesize that inoculation increased salt tolerance in plants through an ABA-independent pathway, and this prevented the stress-dependent ABA accumulation and the resulting growth impairment [63].
\nSarig et al. [93] report that sorghum plants subjected to osmotic stress after their emergence showed decreased damage when colonized by Azospirillum brasilense. It is unclear, however, if the observations were a drought-specific response or an indirect effect of inoculated plants showing a better root development and higher hydraulic conductivity at the time of the stress. In two successive studies [94, 95] conducted on various Azospirillum spp., inoculated wheat plants subjected to drought had decreased grain loss, better water status, and higher K and Ca content, with the latter in particular suggested to be involved in the adaptation of the plants to environmental stress. Bacterial nitrate reductase was also suggested to play an important role in nitrate assimilation of plants under drought [95].
\nAs previously mentioned, drought and saline stress are related, since salinity is often the result of irrigation practices to avoid plant desiccation from drought stress. This concern may become more relevant in future years, as higher temperatures caused by global warming will result in higher evapotranspiration, hence requiring increased irrigation. By the year 2050, 50% of all arable lands might be affected by serious salinization [96]. Improving the resistance of plants to dry environments would decrease the necessity of irrigation, indirectly decreasing the ongoing salinization process in agricultural land.
\nIn natural environments, plants die and decompose where they grew, and the subsequent detritus reintroduces soils with most of the nutrients they absorbed during their growth. In cultivated lands, those nutrients are removed at harvest and must be constantly replaced to avoid productivity decrease. Among the macronutrients, nitrogen, phosphorus, and potassium are the most important for plant growth, and they are typically reintroduced using synthetic fertilizers. Unbalanced use of fertilizers can decrease soil quality, consume organic matter stocks, and increase erosion risk. Soil bacteria can improve the nutritional status of plants directly by increasing nutrient bioavailability and/or indirectly by improving plant root development, hence allowing them to explore higher areas of soil [97].
\nSeveral bacterial species are classified as diazotrophs, which are microorganisms that are able to utilize the nitrogenase enzyme to fix atmospheric N2. Diazotrophic bacteria can fix N2 in either a free-living form or in association with a host as an endosymbiont. The most well-described interaction between plants and diazotrophic bacteria is the rhizobia-legume symbiosis. Rhizobia are a group of various Proteobacteria that can colonize plant roots and fix atmospheric nitrogen, which is then partly provided to the plant in exchange of photosynthates [98]. While this association has been observed mainly in legumes, some species of rhizobia can also colonize cereals. Gutierrez-Zamora and Martinez-Romero [99] showed how maize and bean plants cultivated in association shared the same Rhizobium etli strains, with the bean plants probably constituting the source of inoculum for maize. The interaction with the rhizobia increased the biomass of both crops, but in maize this outcome might have been linked to mechanisms other than N2 fixation, such as hormone production. Rice inoculated with an Azoarcus sp. showed improved growth regardless of colonization by the wild-type strain or with a mutant strain deficient in the nitrogenase genes [3]. When spring wheat and maize were inoculated with two different rhizobia and grown at various soil N levels, the two strains were effective in enhancing plant growth only at low and intermediate levels of soil N. The authors suggest that plant growth-promoting hormones released by the bacteria caused a better root development in inoculated plants that were able to absorb more nutrients from the soil [100].
\nIn general, diazotrophic bacteria associated with cereal roots often carry the nitrogenase genes necessary for the fixation of atmospheric nitrogen, but the relative enzymes are not always synthesized inside plant tissues. Furthermore, the amount of fixed N provided to the plant is often negligible, due to low presence of diazotroph bacteria or because bacteria use fixed nitrogen for their own growth [101]. The nitrogenase enzyme cannot function in the presence of O2, so it may be desirable to engineer free-living diazotrophic bacteria that are able to colonize plant tissues. Other possible ways might be to increase the fixing bacteria population by engineering plants capable of exudating diazotroph favorable compounds or engineering bacteria capable of providing the plant with higher levels of nitrogen [102].
\nFox et al. [103] modified a Pseudomonas sp. genome by adding a gene cluster with nitrogenase activity that improved the performance of wheat and maize by fixing N2. This is an example of some of the approaches toward nitrogen-fixing cereals, that is, plants capable of sourcing the N necessary for their growth from the atmosphere via endosymbionts [104].
\nFarmers have benefited from the rhizobia-legume symbiosis for centuries, and extending this characteristic to cereals would be a decisive benefit for modern agriculture, providing a continuous, ecologically, and economically sustainable source of N to the most important crops.
\nDespite the benefits PGPR impart on plant nutrient content, it is often unclear if this improvement is related to an enhanced mineral uptake or if it is the result of improved root system development in inoculated plants due to bacterial hormones and/or enzymes [48].
\nVarious bacterial strains are known to increase bioavailability of phosphorus in soil, due to the mineralization of organic phosphate and solubilization of inorganic phosphate. Some of the bacterial compounds linked to these two processes are acid phosphatases and organic acids, respectively [105]. Phosphate-solubilizing bacteria have been reported to improve the growth of maize [106], rice [107], and wheat [108].
\nPGPR can also synthesize siderophores that are low-molecular-weight compounds with high iron-binding affinity [109] that can complex with Fe (predominantly Fe3+) in soil. The iron-siderophore complex is then assimilated by the bacterium using a complex-specific receptor [110]. This has various effects, it depletes the soil iron supply, thereby preventing the growth of other potentially pathogenic microbes, and, if the iron is then provided to the plant, it can directly improve plant growth [48]. Furthermore, the bacterial nitrogenase activity and nif gene expression are iron dependent [111, 112]; hence, the absorption of iron from the soil enables diazotroph bacteria to convert atmospheric N2 to a form that is bioavailable for the plant.
\nPGPR can indirectly improve plant performance neutralizing the stress-related hormones produced by the plant in poor soils. Wheat plants grown at various levels of N, P, and K, showed increased grain yield and biomass production when colonized by Pseudomonas spp., with the bacterial growth promotion being negatively correlated with the amount of provided nutrients [97]. The authors ascribe this outcome to bacterial production of ACC deaminase that decreased ethylene levels produced by plants as a response to low nutrients levels, which impaired root development in uninoculated plants.
\nOverall, plant growth promotion is ascribed to a combination of multiple mechanisms. Egamberdiyeva [113] inoculated maize seeds with PGPR with nitrogenase and/or IAA activity and grew them on two soil types with different nutrient availabilities. Inoculated plants generally developed a higher root and shoot biomass and had higher N, P, and K contents, the improvement being more pronounced in plants grown on nutrient-poor soils. However, this study did not consider the possible interactions of inoculated strains with the native microbial populations that may have affected the results.
\nIn 2014–2015, out of 182 million metric tons (Mt) of consumed fertilizer, one half was applied to cereals [14]. Cereals consumed more than one half of N fertilizers and more than one third of P and K fertilizers. As previously mentioned, these amendments have both a high economical and environmental cost, as they can cause soil degradation, pollution of water, and eutrophication. While developing N-fixing PGPR is a task yet to be achieved in cereal agriculture, it is well documented how PGPR can improve the efficiency of nutrient uptake in crops. This can occur by either increasing the bioavailability of nutrients in the soil or as a consequence of better root development, resulting in better soil exploration.
\nCereal-PGPR interactions have been widely studied over the last few decades, and the positive influence that they can have on plant growth is still being established. However, the lack of consistency among different studies is still a concern, highlighting that when multiple biological actors are involved, no generalizations can be made. The same bacterial strain can be beneficial to a plant species and damage another [114] or have no effects or even be detrimental for plant performance when the growing conditions are optimal but become beneficial when growing conditions worsen [2, 3, 4]. In two studies on maize and rice subjected to water deficiency [90, 115], the beneficial effects of various bacterial isolates on plant growth increased with the severity of the stress. Studying the interaction between PGPR and gum rockrose (Cistus ladanifer), Solano et al. [116] hypothesized that a possible explanation for this is that poor environments may impair the growth of indigenous microbial communities, this way decreasing the competition for those microbes that establish advantageous relationships with plants. Another possible explanation is that when the main bacterial mechanism of plant growth promotion is providing them with nutrients, the benefit might be limited in nutrient-rich soil, while it can be significant in the case of limiting nutrients [117].
\nThe observed outcomes change particularly from laboratory and climate chamber trials to more open setups such as greenhouses and field, in which bacteria often fail to improve plant growth [37]. Most of the studies conducted so far on the interaction between cereals and PGPR were performed in controlled environments, usually applying only one single stress at a time. While this is a necessary compromise when starting to study this interplay, it often entails a significant bias from realistic field environment [2], in which plants frequently face more variable growing conditions and face multiple stresses at the same time, triggering unique responses in plants that are different from the sum of plant response to stress applied individually [118]. So far, very few experiments have studied the interaction between bacteria and crops under multiple stresses, but replicating as accurately as possible real field conditions is an essential step for understanding and exploiting the role of PGPR in agriculture. In addition to the more unstable growing environment, another important variable added in field experiments is the interaction with the native microbiota. Often inoculated bacteria in the field show lower rhizosphere or root colonization than laboratory, climate chamber, and greenhouse trials [119], in which the growth medium is usually sterilized at the beginning of the experiment.
\nOne of the hypotheses that can be drawn from the current literature is that the origin of the inoculated bacteria is often a decisive factor for the interaction to improve plant growth. Bacteria isolated from the same plant species used in trials are more likely to play a beneficial role, probably due to the plant-specific exudates that have a key role in the early phases of the interaction [100]. Similarly, bacteria isolated from environments characterized as suboptimal (temperature in particular) that are similar to the conditions and stress applied in plant trials may be more beneficial than bacteria isolated from optimal conditions, delivering more benefits to the plant, due to adaptations that allow the bacteria to be more competitive than the native microbiota [72]. Unfortunately, inoculum used in trials may become less effective due to continual cultivation in laboratory environments, and when planning a plant trial, this should be taken into consideration.
\nOne of the problems facing commercialization of PGPR on markets is the inoculation delivery method on plants. In the laboratory, a common method is dip inoculation where seedling roots are immersed in bacterial culture and then transplanted into the growth substrate, but this approach is not feasible for annual cereals on the field scale. The on-field application of bacterial solutions after seedling germination, while less laborious, still requires considerable equipment and technical knowledge. The most feasible way to apply PGPR on field is probably the use of pre-inoculated seeds (this is already used for rhizobia-legume inoculation) allowing farmers to bulk sow, relieving them from the inoculation step. When the seed bacterial treatment is done immediately before germination, the required strength of bacterial inoculum is typically smaller than in seedling treatments, but ideally inoculants should survive long enough on seed coats to be present during germination; however, prolonged survival of microbial treatment on seeds is still a challenge [120]. Moreover, inconsistencies between performances of seed inoculants are often observed in different trials, and further research is required to address this issue [121]. Utilizing vertical transfer of microbial endosymbionts in seeds may also present a possible inoculation technology that has not been explored extensively and may provide economic benefits to farmers [120] and could potentially mitigate the problem of inoculum viability in seed coats. Recently, studies on bacterial strains vertically transmitted in cereal seeds have shown promising plant growth-promoting effects, likely linked to their ability to solubilize phosphorus, produce hormones, siderophores, and ACC deaminase [122]. By exploiting the existing interactions between plants and known seed endophytic bacteria or isolating new bacterial strains capable of inhabiting seeds for vertical transmission by crops, new technologies may emerge that have large-scale economical applications.
\nDuring the last decades, selection of crops has been driven by increased productivity in nutrient-rich environments, with scarce focus on the positive effects of PGPR, and this trend might have led to the loss of plant traits associated with the microbial interaction [5]. The identification and reintroduction of the genes associated with those traits might enhance the positive effects of PGPR, especially in poor environments, and selecting plants that have superior interaction with rhizosphere microbiota should be considered in plant breeding programs. Additionally, a more immediate way to alleviate temperature stress could be to inoculate plants with bacteria originated from hot-climate regions that as a consequence are more likely to help their host to perform better in a warming environment [29, 72].
\nThe interaction with microbes will gain more attention in the future, considering the effects of climate change, due to the microbial genetic plasticity compared to plants. PGPR may evolve rapidly, developing efficient adaptation strategies to the benefit of the plant host as well.
\nAs an Open Access publisher, IntechOpen is dedicated to maintaining the highest ethical standards and principles in publishing. In addition, IntechOpen promotes the highest standards of integrity and ethical behavior in scientific research and peer-review. To maintain these principles IntechOpen has developed basic guidelines to facilitate the avoidance of Conflicts of Interest.
",metaTitle:"Conflicts of Interest Policy",metaDescription:"As an Open Access publisher, IntechOpen is dedicated to maintaining the highest ethical standards and principles in publishing. In addition, IntechOpen promotes the highest standards of integrity and ethical behavior in scientific research and peer-review.",metaKeywords:null,canonicalURL:"/page/conflicts-of-interest-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\\n\\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\\n\\nA Conflict of Interest can be identified at different phases of the publishing process.
\\n\\nIntechOpen requires:
\\n\\nCONFLICT OF INTEREST - AUTHOR
\\n\\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\\n\\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\\n\\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\\n\\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\\n\\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\\n\\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\\n\\nCONFLICT OF INTEREST - REVIEWER
\\n\\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\\n\\nEXAMPLES OF CONFLICTS OF INTEREST:
\\n\\nFINANCIAL AND MATERIAL
\\n\\nNON-FINANCIAL
\\n\\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\\n\\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\\n\\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\\n\\nEXAMPLES:
\\n\\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\\n\\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\\n\\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\\n\\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\\n\\nPolicy last updated: 2016-06-09
\\n"}]'},components:[{type:"htmlEditorComponent",content:"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\n\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\n\nA Conflict of Interest can be identified at different phases of the publishing process.
\n\nIntechOpen requires:
\n\nCONFLICT OF INTEREST - AUTHOR
\n\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\n\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\n\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\n\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\n\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\n\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\n\nCONFLICT OF INTEREST - REVIEWER
\n\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\n\nEXAMPLES OF CONFLICTS OF INTEREST:
\n\nFINANCIAL AND MATERIAL
\n\nNON-FINANCIAL
\n\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\n\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\n\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\n\nEXAMPLES:
\n\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\n\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\n\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\n\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\n\nPolicy last updated: 2016-06-09
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