Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
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This achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
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We are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
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Thank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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\n
1. Introduction
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Non-communicable diseases now account for 75% of deaths globally, with chronic kidney disease (CKD) rapidly rising up the ranks as a cause of death, reaching eleventh on the list in 2016 [1]. The estimated global crude prevalence of CKD in 2016 was 275.9 million cases associated with a crude mortality of 1.2 million [2].
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As CKD patients’ renal function declines, mortality rises to an estimated lifespan of 8 years for patients on dialysis of 40–44 years of age and 4.5 years to patients 60–64 years of age. Improvements in dialysis therapy have been accompanied by a decline in mortality rate [3]. Despite this, the long-term mortality on dialysis remains significantly inferior to that following kidney transplantation.
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A systematic review in 2011 identified 110 studies including nearly 2 million patients with transplantation conferring a mortality advantage over dialysis. Only studies with follow-up periods <3 months favoured dialysis, attributed largely to perioperative complications and higher immunosuppression post-transplantation [4]. Accordingly, transplant and dialysis registry studies have confirmed increased mortality in transplanted patients compared to dialysis at 3 months (HR 2.0, 1.5–2.7, p < 0.001) with reversal at 6 months (HR 0.27, 0.16–0.47, p < 0.001) with 80% reduction in mortality following transplantation compared to dialysis at 12 months [5]. The increase in mortality associated with kidney transplantation highlights the need for optimal perioperative management to minimise the risks and maximise the benefits associated with transplantation. This chapter focuses on the principles and evidence of perioperative management of transplant patients.
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2. Pre-operative transplant management
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2.1 Initial clinical assessment pre-transplant
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Patients on the kidney transplant waiting list have usually undergone a thorough medical and surgical assessment prior to listing to identify significant comorbidities that would preclude transplantation. Optimisation of cardiovascular comorbidities, including diabetes mellitus (DM) and hypertension, is important not only for prevention of cardiovascular disease but also for avoidance of hypertensive and diabetic damage to the transplanted graft. Nevertheless, at the point that an intended recipient is admitted to hospital for transplantation, a thorough reassessment is important to identify any new medical issues, as well as to ensure that the recipient is sufficiently medically stable for a general anaesthetic and surgery.
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On arrival at the transplanting hospital, bloods are collected with a request for the laboratory to process these urgently (Table 1). In addition, a chest radiograph and ECG are performed.
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\n
\n\n
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Blood tests:
Renal and liver chemistry including phosphate, calcium, and LDH
Full blood count
Coagulation profile
Blood group + hold
Serum for tissue typing investigations
Serology for CMV, EBV, VZV, toxoplasma hepatitis B, hepatitis C, HIV
Pregnancy test as appropriate
Urine culture unless anuric
Chest radiograph
Electrocardiogram
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\n
\n\n
Table 1.
Usual investigations for a patient presenting for kidney transplant.
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While these investigations are being processed, a medical history and examination should be undertaken with the patient with the aim of documenting:
Any new medical comorbidities, in particular symptoms suggesting the development of vascular disease (angina, claudication, peripheral ulceration), malignancy (unexpected weight loss, new mass or lymphadenopathy) or active infection (fever, constitutional symptoms).
Signs or symptoms of fluid overload, with assessment of the patient’s weight in relation to their recent clinic weights (or current target weight if on dialysis).
The patient’s usual daily urine volume.
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The presence of potential new medical comorbidities should prompt review of suitability for, and safety of proceeding with transplantation. The development of ischaemic heart disease, vascular disease, malignancy or active infection would preclude proceeding with transplantation.
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A key decision during the assessment is whether a patient requires dialysis prior to transplantation. Similarly, donor factors associated with a high probability of delayed graft function (e.g., donation after circulatory death [DCD] kidney, prolonged anticipated cold ischaemic time) require a lower threshold for dialysis. Significant hyperkalaemia (a typical threshold may be a serum potassium concentration > 5.5 mmol/L) or fluid overload should prompt urgent dialysis prior to transplantation. In general, it is better to control fluid and electrolyte abnormalities effectively with dialysis pre-operatively rather than to attempt dialysis in a less stable patient post-surgery. Due to tissue damage and intraoperative bleeding, hyperkalaemia may worsen post-operatively. If haemodialysis is required prior to transplantation, patients are usually slightly above their target weight with the aim of avoiding intraoperative hypotension. Minimal or no heparin should be administered during dialysis to minimise the risk of perioperative haemorrhage.
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\n
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2.2 Management of pre-existing medication
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Patients with advanced kidney disease are often on multiple medications, many of which can be safely discontinued at the time of transplantation, including most antihypertensive medication, phosphate binders, cinacalcet, and erythropoiesis-stimulating agents. However, some medications should usually be continued as follows:
Active vitamin D compounds in patients post-parathyroidectomy are usually continued. Calcium levels post-transplant follow a biphasic pattern with early decline in the post-operative week without supplementation. The protective effect of raised PTH is absent in patients post-parathyroidectomy, thereby risking precipitating severe hypocalcaemia if such patients are not supplemented with active vitamin D compounds (calcitriol and alfacalcidol) [6].
Beta blockers are usually not stopped abruptly in the perioperative period due to concerns that this may lead to rebound tachycardia and increase the risk of mortality [7]. However, it may be reasonable to reduce the dose and/or convert patients to a beta blocker with a shorter duration of action (e.g., metoprolol) to reduce the risk of hypotension in the post-operative period.
Statins, although generally safe, can predispose to rhabdomyolysis if used in conjunction with CYP450-3A4 inhibitors [8]. We suggest ceasing statins until outside the perioperative period.
Antiplatelet therapy with aspirin is usually continued perioperatively, and many transplant centres routinely prescribe aspirin to recipients who are not already receiving this agent to reduce the risk of transplant vessel thrombosis, although this has a poor evidence base [9]. Dual antiplatelet therapy with aspirin plus agents, such as platelet P2Y12 receptor inhibitors (e.g., clopidogrel and ticagrelor), would usually be considered a contraindication to transplantation, both because of the increased risk of bleeding and the frequent association of significant vascular disease in patients requiring this combination.
Erythropoiesis stimulating agents (ESA) may be continued on the basis of some studies identifying anaemia as an independent predictor of mortality in the intermediate post-transplant period [10]. There are, however, no studies showing benefits of continued ESA therapy or defining optimal haemoglobin targets [11]. European Best Practices Guidelines for anaemia management recommend that ESA not be ceased in patients undergoing surgery, but no specific recommendations are made regarding transplantation [12].
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Potential transplant recipients who are anti-coagulated with warfarin require urgent reversal of anticoagulation prior to surgery. There are often local protocols for warfarin reversal, but a typical approach would be 1–2 mg oral vitamin K administered as soon as the patient presents to hospital, followed by infusion of either fresh frozen plasma or a prothrombin complex concentrate, such as prothrombinex-VF, depending on the INR [13]. Whether intravenous heparin is required post-operatively will depend on the strength of the indication for anticoagulation, the degree of post-operative haemorrhage, and a decision regarding this should be made in consultation with the transplant surgeons. Where the risk of thrombosis is not excessively high, it is preferable to defer recommencing warfarin until at least 4 weeks post-transplant due to the frequent requirement for a transplant biopsy during this period.
\n
Although non-vitamin K oral anticoagulants (NOACs) are currently not used routinely in end-stage kidney disease (ESKD) patients, indications for their use have been expanding into patients with more severe renal dysfunction. Nonetheless, NOACs should be avoided in ESKD patients on the active transplant list.
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\n
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2.3 Pre-operative management of diabetes and hyperglycaemia
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In Australia, over 23% of patients who are listed for a deceased donor transplant have diabetes [ANZDATA 2016]. The presence of autonomic neuropathy should be noted, as this may help predict haemodynamic instability and risk for graft hypoperfusion post-operatively. Similarly, gastroparesis may have important implications for immunosuppressive drug absorption if severe and retinopathy may complicate post-operative medication management if visual acuity is substantially reduced.
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After admission for kidney transplantation, patients with type 2 diabetes should omit hypoglycaemic medication during the period of preoperative fasting, with regular capillary glucose monitoring performed every 1–2 h. Hypoglycaemia is managed with intravenous dextrose. If significant hyperglycaemia develops, an intravenous insulin infusion is the safest method to control glucose levels until the recipient is able to eat post-operatively. Patients with type 1 diabetes should commence an intravenous insulin infusion after admission to hospital to prevent the development of ketoacidosis.
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2.4 Immunosuppression
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After the decision has been made to proceed with a transplant, an immunosuppression regimen is selected. This regimen is usually initiated before the recipient goes to theatre so that immune function is attenuated prior to donor antigen exposure after reperfusion of the allograft. The choice of immunosuppressive regimen is individualised depending on the circumstances of the recipient and, in particular, the perception of immunological risk (Table 2).
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Very low risk
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Identical twin donor
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Low risk
\n
HLA-identical sibling donor, no DSA
\n
\n
\n
Average risk
\n
HLA-mismatched donor, no DSA
\n
\n
\n
High risk
\n
HLA-mismatched donor, detectable DSA, negative cross-match or ABO-incompatible donor following desensitisation
Immunological risk assessment for kidney transplantation.
DSA, donor-specific antibody.
\n
Most patients undergoing kidney transplantation will receive induction immunosuppression, typically consisting of intravenous methylprednisolone combined with either a monoclonal antibody targeting CD25 (the high affinity α-chain of the IL-2 receptor) [14], such as basiliximab, or a lymphocyte-depleting antibody (such as thymoglobulin [15] or alemtuzumab [16, 17, 18]). Induction therapy is combined with ongoing maintenance immunosuppressive therapy, typically consisting of three immunosuppressive agents [19]. The most commonly prescribed combination in Australia and the USA currently is tacrolimus, mycophenolate and prednisolone [20, 21]. ABO-incompatible transplants as well transplants where there is a pre-transplant DSA requiring plasma-exchange prior to transplantation are outside the scope of this chapter. Similarly, special circumstances including steroid-free immunosuppression are not discussed here.
\n
\n
\n
2.5 Prophylactic medications
\n
The administration of immunosuppression needs to be balanced against the increased risk of infection. With ESKD patients being routinely subjected to hospital environments, additional consideration should be given for prophylaxis in patients colonised with multi-resistant organisms. Patients with prior known serious or recurrent infections should be evaluated carefully and assessed for recurrence and presence of occult infection prior to proceeding with transplantation. In addition, gastro-protection, infection and VTE prophylaxis is charted (Table 3).
\n
\n
\n
\n\n
\n
Gastro-protection
\n
Ranitidine (or PPI) therapy while on high dose steroids
\n
\n
\n
Bacterial prophylaxis
\n
Perioperative antibiotic therapy prescribed based on local guidelines and adapted for recipient multi-resistant organism colonization or potential donor infection
Oral nystatin or amphotericin for duration of admission. Optimal duration uncertain
\n
\n
\n
Systemic fungal prophylaxis
\n
Not generally prescribed due to low incidence of invasive fungal infection
\n
\n
\n
CMV prophylaxis
\n
Oral valganciclovir. Duration depending on donor and recipient serostatus—see Table 4
\n
\n
\n
VTE prophylaxis
\n
Unfractionated heparin and mechanical calf compressors unless contraindicated until patient mobile
\n
\n\n
Table 3.
Perioperative prophylaxis.
\n
Despite some controversy for the use of surgical antibiotic prophylaxis, routine prescribing is common, generally following local practices and guidelines [22]. No consensus currently exists for optimal antibacterial prophylaxis, but the general approach is to minimise dose and duration of administration to prevent emergence of antibiotic resistance [23]. A Cochrane systematic review is currently being undertaken to evaluate the evidence for antibiotic prophylaxis in preventing postsurgical site infections in solid organ transplant recipients [24]. Where there are risk factors that may predispose the recipient to bacterial transmission from the donor, such as treated bacteraemia or urine infection, the duration of antibiotic prophylaxis is adapted to cover the appropriate organisms.
\n
Prior to introduction of prophylaxis, PJP was an important cause of severe pneumonia, associated with an estimated 29–50% mortality [25]. Since the widespread use of co-trimoxazole prophylaxis, the incidence of PJP has declined to an estimated incidence of 0.8 case per 1000 person at 1-year post-transplant [26]. Co-trimoxazole prophylaxis is routinely prescribed in most transplant centres for 6–12 months post-transplant and many centres now advocate for continued prophylaxis following PJP outbreaks [27]. If co-trimoxazole is contraindicated, alternative agents are inhaled pentamidine isethionate or oral dapsone.
\n
Prophylaxis against urinary tract infections (UTIs) is usually provided by the co-trimoxazole therapy administered for PJP prophylaxis. On the basis of limited evidence, perioperative UTI prophylaxis is recommended and in the case of co-trimoxazole intolerance, another agent could be chosen [11].
\n
Systemic anti-fungal prophylaxis is not routinely administered to kidney transplant recipients [28]. However, oral nystatin or amphotericin is frequently prescribed in the early post-operative period to reduce the risk of oropharyngeal candida infection [11]. The optimal duration of therapy is unknown, largely due to low event rates, but a typical approach would be therapy for the first month post-transplant [29].
\n
Previous cytomegalovirus (CMV) infection is common, with a seroprevalence of up to 75% in transplant recipients [30]. The risk of developing CMV viraemia post-transplant depends on the serostatus of both donor and recipient as well as the induction immunosuppression agent (Table 4). The highest risk CMV infection is seen in seronegative recipients of a transplant from a seropositive donor, and is increased in patients treated with T cell depleting agents [31].
\n
\n
\n
\n\n
\n
CMV D−R−
\n
Usually no prophylaxis
\n
\n
\n
CMV D+R+ or D−R+
\n
Valganciclovir for 3 months
\n
\n
\n
CMV D+R−
\n
Valganciclovir for 6 months
\n
\n\n
Table 4.
Prophylaxis for cytomegalovirus.
D, donor serostatus; R, recipient serostatus.
\n
Several antiviral agents have been shown to reduce the risk of CMV infection (with the added benefit of also providing prophylaxis against herpes simplex and herpes zoster reactivation) in transplant recipients, including intravenous ganciclovir and oral acyclovir and valganciclovir, irrespective of donor status and induction immunosuppressive regimen [32]. Unfortunately, viral prophylaxis has shown little benefit in reducing the incidence of EBV-related PTLD [33]. Sustained prophylaxis benefit is observed with longer duration therapy (>3 months) with the main adverse effects being leukopenia with longer therapy duration [32]. Due to the observed benefit in reducing the incidence of CMV disease and cost effectiveness, 6 months antiviral prophylaxis is generally prescribed in high-risk CMV D+R− pairs [34]. An accepted alternative approach to universal prophylaxis is to monitor for CMV viraemia regularly post-transplant and initiate pre-emptive therapy should significant viraemia develop [32, 35].
\n
Due to the gastro-erosive effects of prednisolone, ranitidine 150 mg twice daily for gastro-protection is usually recommended, noting the potential risk of interstitial nephritis and chronic kidney disease with proton-pump inhibitors (PPIs) [36, 37]. If ranitidine is contraindicated or ineffective, use of low dose PPIs as second line is recommended.
\n
Deep venous thrombosis (DVT) has not been extensively evaluated in the literature. Kidney transplantation is categorised as a moderate risk group of patients for development of thromboprophylaxis conferring an estimated risk of DVT of 6% [38]. Limited studies have suggested the incidence to be lower with mechanical thromboprophylaxis alone [39]. Despite the lack of evidence, thromboprophylaxis is generally initiated immediately post-operatively in the absence of contraindications or concerns of active haemorrhage. A combination of unfractionated heparin prophylaxis and mechanical calf compression is used, following local guidelines.
\n
\n
\n
\n
3. Intra-operative and immediate post-operative considerations
\n
Although surgical and anaesthetic approaches and considerations are outside the scope of this chapter, intra-operative events have significant impacts on patient and graft outcomes. Review and documentation of intra-operative and immediate post-operative factors can help predict and guide subsequent clinical course (Table 5).
Appearance on cross-clamp release. Intraoperative Dopplers
\n
\n
\n
Haemodynamics
\n
Blood pressure profile, CVP, need for inotropic support, blood loss volume
\n
\n
\n
Fluid balance
\n
Volume of intravenous fluid administration during procedure, urine output
\n
\n
\n
Biochemistry
\n
Intraoperative insulin dextrose. Post-operative renal chemistry panel including urea, creatinine and potassium
\n
\n\n
Table 5.
Post-operative documentation.
Assessment of listed factors helps guide and predict perioperative management
\n
Any surgical complications or anatomical challenges (notably presence of multiple renal arteries, difficult bench surgery and renal capsule tear) should be communicated by the transplant surgeons as these can help predict perioperative complications. If available, intraoperative Doppler assessments should be documented to confirm adequate post-perfusion flow parameters in the transplanted kidney. Where there is perioperative concern regarding allograft perfusion, or early unexpected oligoanuria, an early duplex ultrasound may be requested to confirm flow in the transplant vessels.
\n
Significant blood loss, requirement of inotropic support and intra-operative haemodynamic instability indicate suboptimal organ perfusion and are risk factors for delayed graft function (Section 5.4). Central venous line is placed at the time of surgery, and central venous pressure (CVP) is still used intra-operatively and in the immediate post-operative period. It is important to acknowledge controversies in absolute CVP targets, with studies advocating improved outcomes with high CVP (10–15 mmHg) targets at reperfusion [40, 41] and others observing increased kidney dysfunction with CVP >11 mmHg [42]. In general, intra-operative CVP trends can inform fluid management, but should not form the basis of a fluid management strategy due to inconsistent correlation with intravascular volumes [43].
\n
Despite preoperative optimization, hyperkalaemia is common post-operatively due to tissue trauma and resorption of intra-abdominal blood. The presence of hyperkalaemia >6 mmol/L in the immediate post-operative period should prompt consideration of dialysis depending on the urine output. If graft urine output (with native residual renal function deducted) is >100 mL/h, it may be reasonable to manage the patient medically with insulin-dextrose infusion and loop diuretics. It should also be noted that intraoperative use of insulin-dextrose often results in rebound hyperkalaemia postoperatively.
\n
\n
\n
4. Perioperative fluid management
\n
Optimal fluid management strategy is contentious, although there is good evidence that fluid loading to maintain cardiac output and optimise renal perfusion, improves outcomes [44]. Intra-operative blood losses and fluid balance can be estimated through discussion with the transplant surgeon and anaesthetist and review of anaesthetic chart (Section 3). Currently, no studies on fluid management in the perioperative phase of renal transplantation exist to guide practice. A recent randomised trial demonstrated non-inferiority of a non-restrictive perioperative intravenous fluid strategy in high-risk abdominal surgery in terms of disability-free survival. Furthermore, the restrictive fluid strategy was associated with increased rates of acute kidney injury (8.6 vs. 5.0%. p < 0.001) [45]. Although generalizability to renal transplantation is uncertain, a restrictive fluid strategy should be avoided.
\n
A common strategy for managing post-operative fluid replacement in the hours after kidney transplantation is to replace the urine output from the previous hour plus 30 mL to account for insensible losses. A loop diuretic and/or mannitol is sometimes administered during the transplant surgery to precipitate a diuresis, decreasing requirement for dialysis, but has not been shown to improve graft outcomes [46].
\n
Frequent clinical assessment of the recipient’s fluid status, including the jugular venous pressure, heart rate, blood pressure and urine output, is important to ensure adequate fluid replacement and to avoid volume overload. Traditional parameters and clinical assessment of fluid status, however, may be unreliable due to compromised homeostatic mechanisms in ESKD and the post-ischaemic transplanted kidney [47]. As soon as it is feasible post-transplant, recipients should be weighed with comparison to their preoperative weight as an objective guide to fluid status.
\n
There is currently no evidence supporting one type of intravenous fluid therapy over another, although a pragmatic, registry-based, multi-centre, double-blind, randomised controlled trial comparing balanced crystalloid solution (PlasmaLyte) with 0.9% saline on the incidence of delayed graft function in 800 adults and children with end-stage kidney disease (ESKD) receiving a deceased donor kidney transplant in Australia and New Zealand is currently underway (ACTRN12617000358347).
\n
A good urine output in the early post-transplant period is a helpful indicator of early graft function, although it may not be possible to differentiate allograft urine output from native urine output in recipients who have significant residual renal function. Oligoanuria may be an indicator of delayed graft function or a harbinger of an early complication, especially if the urine output was good initially (Section 5.4). An urgent ultrasound is a useful investigation to assess perfusion of the allograft at the bedside and to check for evidence of ureteric or vascular complications. The presence of hypoechoic fluid collections may indicate haemorrhage or urinary anastomotic leak (Section 5).
\n
Blood tests to monitor serum creatinine and electrolytes are collected immediately post-transplant and then 6–12 h to monitor renal function and exclude hyperkalaemia. Some recipients may develop a significant diuresis, passing over a litre of urine per hour, and in this situation, frequent monitoring of blood tests 4–6 h is recommended to avoid over or under replacement of electrolytes.
\n
\n
\n
5. Early complications
\n
Complications in the perioperative phase are diverse, reflecting pre-existing transplant recipient comorbidities as well as individual surgical challenges. With the potential for there to be few symptoms from the denervated graft, most centres follow a protocol of investigations for early identification of post-transplant complications (Table 6).
\n
\n
\n\n
\n
\n
Blood tests:
Twice daily full blood count and serum biochemistry
Alternate day CNI levels
Daily capillary glucose levels—if abnormal, manage as diabetes mellitus
Post-operative chest radiograph
Duplex ultrasound imaging, usually at days 2–4 post-transplant
MAG3/DTPA renogram as indicated by clinical progress
\n
\n
\n\n
Table 6.
Common post-operative surveillance investigations.
\n
Generally, an early renal transplant duplex ultrasound can identify vascular or anastomotic complications including renal vessel thrombosis or compression. The resistive index (RI) (measured peak systolic velocity—end diastolic velocity/peak systolic velocity), normally, between 0.60 and 0.80, with levels >0.8 suggesting abnormal perfusion of the allograft, is a widely reported measure of allograft perfusion for duplex scans but does not seem to correlate well with renal histology [48]. A positive correlation has been reported between RI and recipient mortality, and the strongest predictor of an elevated RI was recipient age, suggesting that RI may be an indicator of recipient vascular disease [48]. Consequently, although the RI is commonly reported, clinicians need to be aware of its limitations.
\n
Similarly, nuclear medicine imaging, such as a mercaptoacetyltriglycine (MAG3) or diethylenetriamine pentaacetic acid (DTPA) renogram, can assist in the assessment of allograft perfusion and early graft function as well as identify a ureteric anastomotic leak. Radionucleotide scanning may give an indication of the likely duration of delayed graft function [49, 50].
\n
\n
5.1 Haematological, biochemical and metabolic derangement
\n
Electrolyte abnormalities are a frequent occurrence in the early post-transplant period. Perioperative hyperkalaemia is often followed by hypokalaemia due to diuretics and polyuria combined with large volume IV fluid replacement. Hypomagnesaemia is exacerbated by the tubular effects of CNI therapy and is associated with an increased risk of post-transplant diabetes [51, 52]. Hypophosphatemia is almost universal as a consequence of elevated FGF23 and PTH levels [53, 54]. To reduce the chance of arrhythmias, intravenous electrolyte replacement should target potassium levels in the normal range (3.5–5 mmol/L) and a serum magnesium >0.4 mmol/L. Hypophosphatemia is not usually associated with adverse clinical sequelae, but if severe (<0.4 mmol/L) can also be managed with intravenous replacement. Many transplant recipients require ongoing oral replacement of potassium, magnesium and occasionally phosphate in the first few weeks post-transplant, although this may be limited by gastrointestinal adverse effects.
\n
Myelosuppression is commonly observed in post-transplant patients receiving immunosuppressive therapy. Myeloid, lymphoid and erythroid lineages can separately be affected in combination. Investigations focus on identification of the underlying cause for the haematological abnormality, and blood films are often helpful.
\n
Post-operative anaemia is observed in around 40% of kidney transplant recipients due to erythropoietin deficiency, pre-transplant anaemia and intra-operative blood loss [55]. Initial management should focus ruling out haemorrhage as discussed in Section 5.2. The administration of an erythropoiesis-stimulating agent may be appropriate in recipients with poor initial graft function [11].
\n
Lymphopenia and neutropenia are also common after transplantation, typically as a consequence of the medication-related bone marrow suppression associated with anti-proliferative agents (mycophenolate and azathioprine), mTOR inhibitors (sirolimus and everolimus) and antiviral agents such as valganciclovir for CMV prophylaxis [56, 57, 58]. G-CSF is typically administered if the absolute neutrophil count falls below 1000/μL (1.0 × 109/L) to try to avoid a severe neutropenia (neutrophil count <500/μL, or < 0.5 × 109/L), which is associated with a significant risk of severe infections and requires reverse barrier nursing [59]. Alternative causes of neutropenia should also be considered including parvovirus B12 and CMV infection [60].
\n
Thrombocytopenia is comparatively less common, often occurring in conjunction with leukopenia due to bone marrow suppression as previously discussed. More severe thrombocytopenia is a risk factor for bleeding, and platelet transfusion may be necessary if invasive procedures, such as a renal biopsy, are required and the platelet count is <50 × 109/L [61]. An important consideration, if thrombocytopenia is observed post-transplant, is to look for any other evidence of thrombotic microangiopathy (TMA, Table 7) [62]. TMA occurring after transplant may be due to recurrence of primary haemolytic uraemic syndrome, or a de novo problem. Many triggers for de novo TMA post-transplant have been reported, including medication (CNI therapy, particularly in combination with mTOR inhibitors; valacyclovir), and infections (CMV, parvovirus B19) have all been associated with TMA with the potential for graft damage and kidney injury [63, 64, 65].
\n
\n
\n\n
\n
\n
Thrombocytopenia—platelet count <150 × 109/L
Microangiopathic haemolytic anaemia (MAHA)—haemoglobin <10 g/dL with evidence of red cell fragments on blood film (schistocytes)
Elevated lactate dehydrogenase
Elevated reticulocyte count
Elevated bilirubin
Reduced haptoglobin
\n
\n
\n\n
Table 7.
Features of thrombotic microangiopathy on laboratory tests [66].
\n
The post-operative stress response, combined with induction corticosteroid and cyclosporine or tacrolimus therapy, can result in significant perioperative hyperglycaemia even in patients who do not have pre-existing diabetes, with a reported incidence as high as 80–90% in some studies [67, 68] with post-transplant diabetes persisting in 10–45% depending on the definition used [69, 70, 71, 72, 73]. Hyperglycaemia is also associated with rejection in the perioperative period and in the long term carries adverse metabolic outcomes [74]. It is, therefore, important to monitor capillary glucose levels in all patients after kidney transplantation. Due to the contributions of immunosuppressive medications, and depending on other metabolic risk factors (pre-existing impaired glucose tolerance or diabetes, ethnicity, age and obesity) and immune risk, immunotherapy should be individualised [11]. A detailed discussion of the management of post-transplant hyperglycaemia and diabetes is beyond the scope of this chapter.
\n
\n
\n
5.2 Hypotension: haemorrhage, sepsis and cardiac dysfunction
\n
Perioperative hypotension is common and may reflect inadequate intravascular volume, vasoplegia induced by anaesthetic or analgaesic agents or cardiac dysfunction. Management involves perioperative fluid status optimization with judicious administration of fluid boluses while excluding alternative causes of hypotension including haemorrhage, sepsis and cardiac dysfunction. Recipients with persistent hypotension, despite what appears to be adequate fluid replacement, may require temporary inotropic support. Hypovolaemia, even in the absence of hypotension, increases the risk of delayed graft function resulting in worse graft outcomes [75, 76]. As coronary artery disease is common in patients with ESKD, ruling out ischaemic myocardial damage with ECG review and cardiac enzyme assay measurements is essential (Section 5.3).
\n
Haemorrhage is common in the early period of kidney transplantation, frequently occurring within 48 h of surgery with a reported incidence of 15% [77]. Apart from hypotension, bleeding may manifest clinically with increasing surgical drain output, pain or swelling at the site of the transplant or a falling haemoglobin on serial blood tests. Risk factors for perioperative bleeding include difficult bench surgery, uraemic platelet dysfunction and administration of antiplatelet agents or heparin (either as thromboprophylaxis or during haemodialysis). In a retrospective analysis, difficult bench surgery was identified as the most significant risk factor for post-operative haemorrhage with a 4-fold increased risk. The use of antiplatelet drugs pre-transplant conferred a 2-fold increased risk. Additionally, dialysis vintage was also a risk factor, and each year on dialysis was associated with a 2% increased bleeding risk [77].
\n
In the early post-operative phase, clinical features suggestive of haemorrhage should prompt urgent review of haematology profile, and consideration of imaging in liaison with the transplant surgeon. Peri-nephric hematomas may be identified on ultrasound, but deep or retroperitoneal haemorrhage may be difficult to identify requiring computed tomography. The development of a peri-nephric haematoma may lead to allograft compression, which if significant, may impair graft perfusion with increased diastolic pressures despite normal, or near normal, arcuate artery blood flow indices.
\n
Management of perioperative bleeding requires administration of crystalloid fluids together with judicious transfusion of packed red cells to maintain adequate haemodynamic and haemoglobin targets. Transfusions should be minimised as much as possible, as perioperative blood transfusion leads to recipient sensitization and can increase the likelihood of de novo DSA formation [78]. The decision to proceed to surgical drainage should be individualised, following discussion with the transplant surgeon. The presence of a large haematoma, ongoing haemodynamic instability or features suggesting compression of the allograft, would usually lead to surgical re-exploration.
\n
Sepsis should also be considered in the setting of unexplained hypotension. A high index of suspicion for infection should be maintained at all times since transplant recipients may not develop a fever, leukocytosis or raised inflammatory markers because of their immunosuppressed state (Section 5.7).
\n
\n
\n
5.3 Cardiovascular complications
\n
Due to the significant cardiovascular disease burden and risk associated with chronic kidney disease, cardiovascular complications post-renal transplantation are common. In a retrospective cohort study, the most common perioperative cardiovascular complication was arrhythmia (53%), followed by myocardial infarction (26.4%) with congestive heart failure being relatively rare (1%) [79, 80].
\n
Hypertension, although often overlooked as a perioperative complication, is common, occurring in 50–70% of recipients. It is likely driven by multiple factors including pre-existing hypertension associated with ESKD, cessation of previous antihypertensive therapy at the time of transplantation, iatrogenic fluid administration to optimise allograft perfusion, calcineurin inhibitor therapy (CNI) and corticosteroid-related fluid retention [81]. Modification of fluid status, diuretic therapy and administration of dihydropyridine calcium channel blockers are common initial strategies used to control BP in the early post-transplant period. The non-dihydropyridine agents (diltiazem and verapamil) may be used, but have significant interactions with CNI (cyclosporine > tacrolimus) increasing CNI exposure. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are usually avoided in the perioperative period to due to their potential to increase creatinine levels but can be introduced once allograft function has stabilised with appropriate monitoring of creatinine and potassium levels.
\n
Despite pre-transplant screening for ischaemic heart disease, acute coronary syndromes (ACS) are still seen in the peri-transplant period, an indication of the limited sensitivity of non-invasive cardiac testing to detect clinically significant coronary disease in the ESKD population [82, 83]. ACS are a difficult complication to manage in the perioperative setting due to competing clinical priorities, and the potential benefits of antiplatelet and anticoagulant therapy need to be balanced against the risk of bleeding. Evaluation of the impact of the infarct on ventricular function can be assessed by echocardiography. Decisions on the optimal management including the potential need for angiography should be discussed with the local cardiology team.
\n
Pre-existing congestive cardiac failure should be identified pre-transplantation and optimised through high-quality dialysis to control uraemia and volume overload as well as medical therapy. Large fluctuations in blood pressure and inter-dialytic weight gain will adversely affect myocardial function through cardiomyopathic remodelling and vasoactive humoral-mediated increases in vascular tone and damage. It is important to acknowledge controversies surrounding optimal blood pressure targets in dialysis patients and to individualise both blood pressure target and pharmacological hypertensive therapy [84, 85].
\n
\n
\n
5.4 Delayed graft function
\n
Delayed graft function (DGF) is a form of acute kidney injury and is usually defined as the need for dialysis post-transplant. DGF is associated with a higher incidence of acute rejection as well as poorer allograft survival, with a reported 40% greater risk of allograft loss and higher mean serum creatinine concentration [86, 87]. The reported frequency varies significantly (from 2 to 50%) due to heterogeneity of recipient and donor factors and definition of the event [75]. In Australia and New Zealand, nephrologist reported DGF is present in 19.5% of cadaveric renal transplants [ANZDATA 1997–2014].
\n
Post-operative oliguria, failure of improvement of serum creatinine or the need for dialysis should prompt investigations to identify reversible causes of acute kidney injury, including assessment of risk factors for ATN, recipient hypotension or hypovolaemia, presence of post-surgical vascular or urological complications and rejection. In addition to a review of fluid status, haemodynamic parameters and the timing of a decrease in urine output, the following testing should be considered:
Repeat serum biochemistry and haematology profile to rule out pre-renal kidney injury from anaemia and sepsis, taking account of haemoglobin and haematocrit fluctuations with fluid status dilution and unpredictable inflammatory response in the context of immunosuppression.
Repeat CNI trough levels and review of CNI dosing and trends. These are nephrotoxic and may necessitate adjustment depending on the immune risk of the transplanted patient.
Ultrasound duplex scan to rule out renovascular pathology. This also allows exclusion of peri-nephric collections and obstructive uropathy.
Functional nuclear medical imaging, such as a MAG3, scan will allow assessment of perfusion, graft tracer uptake, and excretion.
A renal biopsy is usually undertaken if DGF persists at day 5 post-transplant to rule out rejection, and is repeated weekly until there are signs of improving allograft function.
\n
It is also helpful to consider risk factors associated with DGF in order to risk stratify and anticipate the clinical course of the transplanted patient (Table 8) [75].
\n
\n
\n
\n\n
\n
Risk factor
\n
Relative impact
\n
\n\n\n
\n
Donation after circulatory death
\n
2× higher rate of ATN. No difference in outcome at 1 year
\n
\n
\n
Donor on inotropes
\n
Early function 58% (vs. 83%). 1-year survival 73% (vs. 91%)
\n
\n
\n
Cold ischemia time
\n
23% increase risk of DGF for every 6 h
\n
\n
\n
Donor age > 55y
\n
2× higher rate of DGF
\n
\n
\n
Other donor factors
\n
Poor reperfusion, death from stroke, presence of AKI associated with increased risk
\n
\n
\n
Higher PRA%
\n
Associated higher risk of requiring dialysis post-transplant
\n
\n
\n
Recipient hypovolaemia
\n
Lower pre-operative DBP, intra-operative albumin requirement and pre-operative haemodialysis with UF
\n
\n
\n
Dialysis modality
\n
Higher rate of DGF in haemodialysis vs. peritoneal dialysis
In the setting of DGF, ongoing dialysis is often required. In haemodialysis patients, every effort should be made to preserve haemodialysis access. If haemodialysis is delivered through a central vascular catheter, this access should be preserved for this purpose alone and additional central access obtained as needed. If the peritoneum is breached in a peritoneal dialysis patient, alternative access for dialysis needs to be considered as peritoneal dialysis is less likely to be successful.
\n
Depending on the immunological risk of the patient, in the presence of DGF, a reduction in target tacrolimus levels can be contemplated. Many transplant centres target a tacrolimus level 8–10 μg/L in the peri-transplantation period. Provided the patient is not considered high immunological risk, reduction of the target range could be considered. The use of thymoglobulin in the setting of DGF is controversial in the absence of immunological risk factors advocating its use as an induction agent [15].
\n
\n
\n
5.5 Renal vascular complication
\n
In transplant recipients who have established a good urine output post-operatively, the sudden development of oliguria or anuria should prompt a review of urinary catheter patency as well as raise the possibility of transplant vessel pathology. Early vascular pathology may be caused by structural or anatomical factors such as vessel kinking, anatomically disadvantageous configurations putting traction on the recipient vessels or thrombosis. Distinguishing between the various pathologies can be challenging clinically, with reliance on duplex ultrasound imaging and knowledge of donor vascular pathology through collaboration with transplant surgeons.
\n
Renal transplant artery or vein thrombosis is a serious, although fortunately uncommon peri-transplant complication, with an incidence of 2–3%, classically occurring in the first week post-transplant [77]. Clinical features of transplant artery thrombosis are typically limited to the sudden onset of oligoanuria, while transplant vein thrombosis may cause allograft swelling, pain and frank haematuria in addition. Predisposing risk factors are decreased perfusion pressures and hypotension as well as donor factors—difficult bench surgery, multiple vessels, prolonged cold ischaemia time and vessel atherosclerosis [77, 88]. Rarer recipient risk factors, when present, can dramatically increase the risk of thrombosis, including in the transplant vessels. Recipients with thrombophilia, notably factor V Leiden mutation or anti-phospholipid antibodies, have been associated with higher risk (2.87 increased risk in one study) of adverse graft outcomes [89, 90]. Diagnosis of transplant vessel pathology may be obtained by urgent renal duplex ultrasonography; however, the abrupt onset of anuria in the early post-operative period is an indication for urgent surgical review and consideration of surgical re-exploration, due to the very short window after transplant arterial thrombosis before irretrievable graft loss occurs.
\n
Renal transplant artery stenosis tends to be a later complication but can occasionally manifest in the perioperative period. The classical clinical features associated with stenosis of the transplant artery are hypertension, allograft dysfunction and fluid overload due to salt and water retention. Risk factors for early transplant artery stenosis tend to be donor related with atherosclerotic vessels or difficult bench surgery [77]. An association with acute rejection has also been described [91]. Diagnosis is by duplex scan showing increased velocity across the anastomotic sites and a flow differential between the aorta and transplant artery.
\n
Intermittent vessel kinking caused by allograft nephroptosis can be diagnostically challenging due to the positional nature of the pathology [92]. Duplex scans may be non-diagnostic, and performing imaging in a non-prone position may assist in the diagnosis of positional vessel compression or kinking, and CT angiography may provide additional diagnostic information in this situation.
\n
\n
\n
5.6 Renal ureteric complications
\n
Ureteric pathology is more common than vascular pathology, but rarely affects graft survival [93]. The most common early urological complication is a urine leak with an estimated incidence of 8%, followed by ureteric stenoses with a similar incidence occurring later in the transplant course [77, 94]. Other complications of vesicoureteric reflux and urolithiasis are uncommon [95].
\n
Ureteric leaks, like vascular pathology, typically occur in first few weeks post-transplant and may present with localised pain or swelling at the site of the allograft, increased surgical drain output or a peri-transplant collection seen on imaging [95]. Non-technical risk factors include recipient agent, pre-transplant urological pathology, immunosuppressive regimen and donor factors [94].
\n
When there is a clinical suspicion for a urine leak due to increased surgical drain output, or if a peri-transplant collection is drained, the fluid should be sent for creatinine concentration analysis to differentiate serous or lymphatic fluid (which will have a similar creatinine concentration to the blood) from urine. Following drain removal, recipients with a urine leak may complain of pain due to fluid accumulation or if there is a significant urine leak, graft function will appear to deteriorate due to reabsorption of urinary creatinine and urea.
\n
The management of urine leaks can be complex and often requires liaison with a transplant urologist. It may be possible to manage minor urine leaks conservatively via bladder decompression with an indwelling catheter in addition to ureteric stenting to allow the distal anastomosis to heal. Larger leaks may require further investigation in contrast to enhanced computer tomography, insertion of a percutaneous nephrostomy or surgical repair [95]. A more detailed discussion of this topic is beyond the scope of this chapter.
\n
\n
\n
5.7 Infection
\n
As a consequence of induction immunosuppression, transplant patients are particularly prone to infection in the perioperative phase. However, sepsis can be challenging to diagnose during this period because immunocompromised patients may not manifest the typical features of a systemic inflammatory response. Due to steroid therapy, most patients will exhibit a peripheral neutrophilia. In general, any change in physiological parameters, clinical deterioration or a temperature > 37.5°C should prompt consideration of sepsis, and a sepsis screen should be requested including [96]:
empiric antibiotic therapy within 1 h of suspected sepsis diagnosis
\n
Although transplant recipients are susceptible to opportunistic pathogens such as CMV, EBV, mycobacteria, Pneumocystis jiroveci and fungi, these are unusual in the early post-transplant period. Infections occurring soon after transplantation are frequently nosocomial, associated with hospitalisation, intravenous and urinary catheters and intubation during surgery. In some instances, infection may be donor derived [97].
\n
\n
5.7.1 Bacterial infection
\n
Urinary tract infections (UTI) are the most common cause of bacterial infection requiring hospitalisation in transplant patients, followed by pneumonia, surgical site infections and septicaemia [98]. Retrospective database studies have estimated a cumulative incidence of 17% in the first 6 months post-transplant, which rises to 60% for women and 47% for men at 3 years [99]. The presentation for UTI is similar to that of the general population and management identical to complicated UTIs with 7–14 days of antibiotic therapy, although the optimal duration has not been well established [98]. Management of post-transplant candiduria is controversial, without definite improvement in clinical outcomes following therapy [100]. Other bacterial pathologies are treated in the same way as in the general population with anticipated more frequent and longer duration antibiotic use due to physician concern over immunosuppressed state and propensity for more severe infection.
\n
\n
\n
\n
5.8 Rejection
\n
In the early era of transplantation, hyperacute rejection due to the presence of preformed donor-specific antibodies (DSAs) occurring in the first minutes or hours after perfusion of the transplant was a significant risk. However, with the introduction of the complement-dependent cytotoxic cross-match, as described by Patel and Terasaki [101], and more recently solid phase assays that are able to detect DSAs with high sensitivity, hyperacute rejection is now extremely rare [102]. Nevertheless, early acute rejection remains a common occurrence, with a reported incidence of 7–25% depending on the level of immunological risk and choice of induction immunosuppression [21, 103, 104, 105, 106]. Contemporary rejection rates in Australia and New Zealand are shown in Table 9.
\n
\n
\n
\n
\n\n
\n
\n
First allograft (%)
\n
Second or subsequent allograft (%)
\n
\n\n\n
\n
Living donor
\n
17.4
\n
16.7
\n
\n
\n
Deceased donor
\n
15.2
\n
18.6
\n
\n\n
Table 9.
Acute rejection rates in the first six months post-transplant.
Data from ANZDATA Registry. 41st Report, Chapter 7: Kidney Transplantation. Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia. 2018. http://www.anzdata.org.au.
\n
In the perioperative period, DGF persisting beyond 4–5 days, decreasing urine output or an unexplained rise in creatinine by >15–20%, should prompt consideration of rejection as the underlying cause (Section 5.4). Unless there is a contraindication such as active bleeding or an unavoidable requirement for anticoagulation, the diagnosis requires a renal biopsy, both to exclude alternative causes of graft dysfunction and to characterise the histological pattern and severity of rejection. Rejection is classified histologically using the Banff criteria into borderline rejection, cell-mediated rejection, antibody-mediated rejection and mixed rejection [107, 108]. Treatment of cellular rejection would usually involve pulsed methylprednisolone 0.25–1.0 g daily for 3 days as first-line treatment, combined with a T-cell depleting therapy such as thymoglobulin/ATG if the rejection is histologically severe rejection (Banff class 2 or greater), or if there is a suboptimal response to methylprednisolone [109]. The optimal therapy for acute antibody-mediated rejection remains unclear, but would typically include pulsed methylprednisolone, plasma exchange (often combined with intravenous immunoglobulin at a dose of 0.1 g/kg following each exchange) outcomes [110, 111, 112]. Some centres also advocate the use of a B cell depleting antibody such as rituximab or the proteasome inhibitor bortezomib, although currently there is no strong evidence that these agents improve clinical outcomes [111, 113, 114, 115].
\n
\n
\n
\n
6. Conclusions
\n
Kidney transplantation has evolved from a highly experimental therapy to become recognised as the gold standard treatment for many patients with ESKD [116]. This progress has occurred through the many iterative developments in the surgical and medical management of transplant recipients, not the least of which being the introduction of highly effective immunosuppressive agents. Delivering high standards of clinical care during the perioperative period is a crucial step in achieving excellent allograft outcomes. This chapter provides an overview of the approach to assessing potential recipients admitted for transplantation, and guidance on typical perioperative medication and fluid prescriptions, as well as post-operative monitoring and early complications.
\n
\n
Conflict of interest
David Johnson has previously received consultancy fees, research grants, speaker’s honoraria and travel sponsorships from Baxter Healthcare and Fresenius Medical Care. He has also received consultancy fees from Astra Zeneca and travel sponsorships from Amgen. He is a current recipient of an Australian National Health and Medical Research Council Practitioner Fellowship. Carmel Hawley has received a research grant from Baxter Healthcare. Ross Francis has received honoraria and travel sponsorships from Novartis, Astellas and Amgen. The other authors have no conflict of interest to declare.
\n
Notes/thanks/other declarations
\n
Nil.
\n
\n',keywords:"comorbidity, kidney transplantation, perioperative care, risk assessment, treatment outcome",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65660.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65660.xml",downloadPdfUrl:"/chapter/pdf-download/65660",previewPdfUrl:"/chapter/pdf-preview/65660",totalDownloads:1858,totalViews:0,totalCrossrefCites:2,totalDimensionsCites:3,totalAltmetricsMentions:0,introChapter:null,impactScore:2,impactScorePercentile:77,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"November 5th 2018",dateReviewed:"January 14th 2019",datePrePublished:"February 15th 2019",datePublished:"October 2nd 2019",dateFinished:"February 14th 2019",readingETA:"0",abstract:"Transplantation carries significant mortality benefit compared to dialysis in end-stage kidney disease. Increased perioperative risk, however, results in a higher mortality in the first 3 months post-transplantation compared to remaining on haemodialysis. Consequently, optimal perioperative management is essential. Patients presenting for kidney transplantation require rapid assessment and preparation for theatre to minimise ischaemic times and improve mortality and graft outcomes. This task is often complicated by the presence of multiple medical comorbidities. Furthermore, early complications of hypotension, delayed graft function, renovascular and ureteric surgical complications and rejection render the perioperative phase of transplant challenging for the recipient and for the transplant team. In this chapter, we outline current practices in the assessment and management of kidney transplant recipients during the perioperative period, particularly focusing on their clinical application and the evidence underpinning them.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65660",risUrl:"/chapter/ris/65660",book:{id:"7877",slug:"perioperative-care-for-organ-transplant-recipient"},signatures:"Sebastian Hultin, Carmel M. Hawley, David W. Johnson and Ross S. Francis",authors:[{id:"172329",title:"Dr.",name:"Carmel",middleName:null,surname:"Hawley",fullName:"Carmel Hawley",slug:"carmel-hawley",email:"carmel.hawley@health.qld.gov.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Gold Coast Hospital",institutionURL:null,country:{name:"Australia"}}},{id:"172331",title:"Dr.",name:"Ross",middleName:null,surname:"Francis",fullName:"Ross Francis",slug:"ross-francis",email:"ross.francis@health.qld.gov.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Gold Coast Hospital",institutionURL:null,country:{name:"Australia"}}},{id:"178936",title:"Prof.",name:"David",middleName:null,surname:"Johnson",fullName:"David Johnson",slug:"david-johnson",email:"david.johnson2@health.qld.gov.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},{id:"283620",title:"Dr.",name:"Sebastian",middleName:null,surname:"Hultin",fullName:"Sebastian Hultin",slug:"sebastian-hultin",email:"sebastian.hultin@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Pre-operative transplant management",level:"1"},{id:"sec_2_2",title:"2.1 Initial clinical assessment pre-transplant",level:"2"},{id:"sec_3_2",title:"2.2 Management of pre-existing medication",level:"2"},{id:"sec_4_2",title:"2.3 Pre-operative management of diabetes and hyperglycaemia",level:"2"},{id:"sec_5_2",title:"2.4 Immunosuppression",level:"2"},{id:"sec_6_2",title:"2.5 Prophylactic medications",level:"2"},{id:"sec_8",title:"3. Intra-operative and immediate post-operative considerations",level:"1"},{id:"sec_9",title:"4. Perioperative fluid management",level:"1"},{id:"sec_10",title:"5. Early complications",level:"1"},{id:"sec_10_2",title:"5.1 Haematological, biochemical and metabolic derangement",level:"2"},{id:"sec_11_2",title:"5.2 Hypotension: haemorrhage, sepsis and cardiac dysfunction",level:"2"},{id:"sec_12_2",title:"5.3 Cardiovascular complications",level:"2"},{id:"sec_13_2",title:"5.4 Delayed graft function",level:"2"},{id:"sec_14_2",title:"5.5 Renal vascular complication",level:"2"},{id:"sec_15_2",title:"5.6 Renal ureteric complications",level:"2"},{id:"sec_16_2",title:"5.7 Infection",level:"2"},{id:"sec_16_3",title:"5.7.1 Bacterial infection",level:"3"},{id:"sec_18_2",title:"5.8 Rejection",level:"2"},{id:"sec_20",title:"6. Conclusions",level:"1"},{id:"sec_24",title:"Conflict of interest",level:"1"},{id:"sec_21",title:"Notes/thanks/other declarations",level:"1"}],chapterReferences:[{id:"B1",body:'Jha V, Modi GK. Getting to know the enemy better-the global burden of chronic kidney disease. 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Infectious disease prophylaxis in renal transplant patients: A survey of US transplant centers. Clinical Transplantation. 2002;16(1):1-8\n'},{id:"B23",body:'Orlando G, Manzia TM, Sorge R, Iaria G, Angelico R, Sforza D, et al. One-shot versus multidose perioperative antibiotic prophylaxis after kidney transplantation: A randomized, controlled clinical trial. Surgery. 2015;157(1):104-110\n'},{id:"B24",body:'Chan SNS, Chan HP, Pascoe E, Playford E, Wong G, Chapman JR, et al. Perioperative antibiotics for preventing post-surgical site infections in solid organ transplant recipients. Cochrane Database of Systematic Reviews. 2018;(12)\n'},{id:"B25",body:'Martin SI, Fishman JA, Practice ASTIDCo. Pneumocystis pneumonia in solid organ transplantation. American Journal of Transplantation. 2013;13(Suppl 4):272-279\n'},{id:"B26",body:'Gordon SM, LaRosa SP, Kalmadi S, Arroliga AC, Avery RK, Truesdell-LaRosa L, et al. Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 1999;28(2):240-246\n'},{id:"B27",body:'Chapman JR, Marriott DJ, Chen SC, MacDonald PS. Post-transplant Pneumocystis jirovecii pneumonia—A re-emerged public health problem? Kidney International. 2013;84(2):240-243\n'},{id:"B28",body:'Playford EG, Webster AC, Sorell TC, Craig JC. Antifungal agents for preventing fungal infections in solid organ transplant recipients. Cochrane Database of Systematic Reviews. 2004;3:CD004291\n'},{id:"B29",body:'Guerra CM, Formica RN, Kulkarni S, Asch WS, Tichy EM. Duration of prophylaxis against fungal infection in kidney transplant recipients. Progress in Transplantation (Aliso Viejo, Calif). 2015;25(4):311-315\n'},{id:"B30",body:'Fishman JA, Emery V, Freeman R, Pascual M, Rostaing L, Schlitt HJ, et al. Cytomegalovirus in transplantation—Challenging the status quo. Clinical Transplantation. 2007;21(2):149-158\n'},{id:"B31",body:'Hodson EM, Ladhani M, Webster AC, Strippoli GF, Craig JC. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. The Cochrane Database of Systematic Reviews. 2013;(2):Cd003774\n'},{id:"B32",body:'Hodson EM, Craig JC, Strippoli GF, Webster AC. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. The Cochrane Database of Systematic Reviews. 2008;(2):Cd003774\n'},{id:"B33",body:'AlDabbagh MA, Gitman MR, Kumar D, Humar A, Rotstein C, Husain S. The role of antiviral prophylaxis for the prevention of Epstein-Barr virus-associated posttransplant lymphoproliferative disease in solid organ transplant recipients: A systematic review. American Journal of Transplantation. 2017;17(3):770-781\n'},{id:"B34",body:'Luan FL, Stuckey LJ, Park JM, Kaul D, Cibrik D, Ojo A. Six-month prophylaxis is cost effective in transplant patients at high risk for cytomegalovirus infection. Journal of the American Society of Nephrology: JASN. 2009;20(11):2449-2458\n'},{id:"B35",body:'Owers DS, Webster AC, Strippoli GF, Kable K, Hodson EM. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. The Cochrane Database of Systematic Reviews. 2013;(2):Cd005133\n'},{id:"B36",body:'Ray S, Delaney M, Muller AF. Proton pump inhibitors and acute interstitial nephritis. BMJ (Clinical Research Ed). 2010;341:c4412\n'},{id:"B37",body:'Rodriguez-Poncelas A, Barcelo MA, Saez M, Coll-de-Tuero G. Duration and dosing of Proton Pump Inhibitors associated with high incidence of chronic kidney disease in population-based cohort. PLoS One. 2018;13(10):e0204231\n'},{id:"B38",body:'Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. 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Do intraoperative hemodynamic factors of the recipient influence renal graft function? Transplantation Proceedings. 2012;44(6):1800-1803\n'},{id:"B43",body:'Marik PE, Cavallazzi R. Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Critical Care Medicine. 2013;41(7):1774-1781\n'},{id:"B44",body:'Brienza N, Giglio MT, Marucci M, Fiore T. Does perioperative hemodynamic optimization protect renal function in surgical patients? A meta-analytic study. Critical Care Medicine. 2009;37(6):2079-2090\n'},{id:"B45",body:'Myles PS, Bellomo R, Corcoran T, Forbes A, Peyton P, Story D, et al. Restrictive versus liberal fluid therapy for major abdominal surgery. The New England Journal of Medicine. 2018;378(24):2263-2274\n'},{id:"B46",body:'Weimar W, Geerlings W, Bijnen AB, Obertop H, van Urk H, Lameijer LD, et al. A controlled study on the effect of mannitol on immediate renal function after cadaver donor kidney transplantation. 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American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2004;4(4):611-620\n'},{id:"B59",body:'Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2000;18(20):3558-3585\n'},{id:"B60",body:'Eid AJ, Chen SF, Practice ASTIDCo. Human parvovirus B19 in solid organ transplantation. American Journal of Transplantation. 2013;13(Suppl 4):201-205\n'},{id:"B61",body:'Warner MA, Woodrum D, Hanson A, Schroeder DR, Wilson G, Kor DJ. Preprocedural platelet transfusion for patients with thrombocytopenia undergoing interventional radiology procedures is not associated with reduced bleeding complications. 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Nephrology (Carlton, Vic.). 2018;23(6):507-517\n'},{id:"B67",body:'Hecking M, Werzowa J, Haidinger M, Horl WH, Pascual J, Budde K, et al. Novel views on new-onset diabetes after transplantation: Development, prevention and treatment. Nephrology, Dialysis, Transplantation. 2013;28(3):550-566\n'},{id:"B68",body:'Chakkera HA, Knowler WC, Devarapalli Y, Weil EJ, Heilman RL, Dueck A, et al. Relationship between inpatient hyperglycemia and insulin treatment after kidney transplantation and future new onset diabetes mellitus. Clinical Journal of the American Society of Nephrology. 2010;5(9):1669-1675\n'},{id:"B69",body:'Cosio FG, Kudva Y, van der Velde M, Larson TS, Textor SC, Griffin MD, et al. New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney International. 2005;67(6):2415-2421\n'},{id:"B70",body:'Mourad G, Glyda M, Albano L, Viklicky O, Merville P, Tyden G, et al. Incidence of posttransplantation diabetes mellitus in de novo kidney transplant recipients receiving prolonged-release tacrolimus-based immunosuppression with 2 different corticosteroid minimization strategies: ADVANCE, a randomized controlled trial. Transplantation. 2017;101(8):1924-1934\n'},{id:"B71",body:'Yates CJ, Fourlanos S, Colman PG, Cohney SJ. Screening for new-onset diabetes after kidney transplantation: Limitations of fasting glucose and advantages of afternoon glucose and glycated hemoglobin. Transplantation. 2013;96(8):726-731\n'},{id:"B72",body:'First MR, Dhadda S, Croy R, Holman J, Fitzsimmons WE. New-onset diabetes after transplantation (NODAT): An evaluation of definitions in clinical trials. Transplantation. 2013;96(1):58-64\n'},{id:"B73",body:'Yates CJ, Fourlanos S, Hjelmesaeth J, Colman PG, Cohney SJ. New-onset diabetes after kidney transplantation-changes and challenges. American Journal of Transplantation. 2012;12(4):820-828\n'},{id:"B74",body:'Thomas MC, Moran J, Mathew TH, Russ GR, Rao MM. Early perioperative hyperglycaemia and renal allograft rejection in patients without diabetes. BMC Nephrology. 2000;1:1\n'},{id:"B75",body:'Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet (London, England). 2004;364(9447):1814-1827\n'},{id:"B76",body:'Dawidson IJ, Sandor ZF, Coorpender L, Palmer B, Peters P, Lu C, et al. Intraoperative albumin administration affects the outcome of cadaver renal transplantation. Transplantation. 1992;53(4):774-782\n'},{id:"B77",body:'Hernandez D, Rufino M, Armas S, Gonzalez A, Gutierrez P, Barbero P, et al. Retrospective analysis of surgical complications following cadaveric kidney transplantation in the modern transplant era. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association. 2006;21(10):2908-2915\n'},{id:"B78",body:'Ferrandiz I, Congy-Jolivet N, Del Bello A, Debiol B, Trebern-Launay K, Esposito L, et al. Impact of early blood transfusion after kidney transplantation on the incidence of donor-specific anti-HLA antibodies. American Journal of Transplantation. 2016;16(9):2661-2669\n'},{id:"B79",body:'Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. Hypoalbuminemia, cardiac morbidity, and mortality in end-stage renal disease. Journal of the American Society of Nephrology: JASN. 1996;7(5):728-736\n'},{id:"B80",body:'Humar A, Kerr SR, Ramcharan T, Gillingham KJ, Matas AJ. Perioperative cardiac morbidity in kidney transplant recipients: Incidence and risk factors. Clinical Transplantation. 2001;15(3):154-158\n'},{id:"B81",body:'Hoorn EJ, Walsh SB, McCormick JA, Furstenberg A, Yang CL, Roeschel T, et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nature Medicine. 2011;17(10):1304-1309\n'},{id:"B82",body:'Wang LW, Fahim MA, Hayen A, Mitchell RL, Baines L, Lord S, et al. Cardiac testing for coronary artery disease in potential kidney transplant recipients. The Cochrane Database of Systematic Reviews. 2011;(12):Cd008691\n'},{id:"B83",body:'Herzog CA, Marwick TH, Pheley AM, White CW, Rao VK, Dick CD. Dobutamine stress echocardiography for the detection of significant coronary artery disease in renal transplant candidates. American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 1999;33(6):1080-1090\n'},{id:"B84",body:'Stidley CA, Hunt WC, Tentori F, Schmidt D, Rohrscheib M, Paine S, et al. Changing relationship of blood pressure with mortality over time among hemodialysis patients. Journal of the American Society of Nephrology: JASN. 2006;17(2):513-520\n'},{id:"B85",body:'Wheeler DC, Becker GJ. Summary of KDIGO guideline. What do we really know about management of blood pressure in patients with chronic kidney disease? Kidney International. 2013;83(3):377-383\n'},{id:"B86",body:'Lim WH, Johnson DW, Teixeira-Pinto A, Wong G. Association between duration of delayed graft function, acute rejection and allograft outcome after deceased donor kidney transplantation. Transplantation. 2018\n'},{id:"B87",body:'Yarlagadda SG, Coca SG, Formica RN Jr, Poggio ED, Parikh CR. Association between delayed graft function and allograft and patient survival: A systematic review and meta-analysis. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association. 2009;24(3):1039-1047\n'},{id:"B88",body:'Bakir N, Sluiter WJ, Ploeg RJ, van Son WJ, Tegzess AM. Primary renal graft thrombosis. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association. 1996;11(1):140-147\n'},{id:"B89",body:'Wagenknecht DR, Becker DG, LeFor WM, McIntyre JA. Antiphospholipid antibodies are a risk factor for early renal allograft failure. Transplantation. 1999;68(2):241-246\n'},{id:"B90",body:'Hocher B, Slowinski T, Hauser I, Vetter B, Fritsche L, Bachert D, et al. Association of factor V Leiden mutation with delayed graft function, acute rejection episodes and long-term graft dysfunction in kidney transplant recipients. Thrombosis and Haemostasis. 2002;87(2):194-198\n'},{id:"B91",body:'Buturovic-Ponikvar J. Renal transplant artery stenosis. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association. 2003;18(Suppl 5):v74-v77\n'},{id:"B92",body:'Dosch AR, Pahl M, Reddy U, Foster CE 3rd, Ichii H. Post-transplantation nephroptosis causing recurrent episodes of acute renal failure and hypertension secondary to intermittent vascular torsion of intraperitoneal renal allograft. Journal of Surgical Case Reports. 2017;2017(5):rjx033\n'},{id:"B93",body:'van Roijen JH, Kirkels WJ, Zietse R, Roodnat JI, Weimar W, Ijzermans JN. Long-term graft survival after urological complications of 695 kidney transplantations. The Journal of Urology. 2001;165(6 Pt 1):1884-1887\n'},{id:"B94",body:'Rodriguez Faba O, Boissier R, Budde K, Figueiredo A, Taylor CF, Hevia V, et al. European association of urology guidelines on renal transplantation: Update 2018. European Urology Focus. 2018;4(2):208-215\n'},{id:"B95",body:'Branchereau J, Karam G. Management of urologic complications of renal transplantation. European Urology Supplements. 2016;15(9):408-414\n'},{id:"B96",body:'Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Medicine. 2017;43(3):304-377\n'},{id:"B97",body:'White SL, Rawlinson W, Boan P, Sheppeard V, Wong G, Waller K, et al. Infectious disease transmission in solid organ transplantation. Donor Evaluation, Recipient Risk, and Outcomes of Transmission. Transplantation Direct. 2019;5(1):e416\n'},{id:"B98",body:'Karuthu S, Blumberg EA. Common infections in kidney transplant recipients. Clinical Journal of the American Society of Nephrology: CJASN. 2012;7(12):2058-2070\n'},{id:"B99",body:'Abbott KC, Swanson SJ, Richter ER, Bohen EM, Agodoa LY, Peters TG, et al. Late urinary tract infection after renal transplantation in the United States. American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 2004;44(2):353-362\n'},{id:"B100",body:'Safdar N, Slattery WR, Knasinski V, Gangnon RE, Li Z, Pirsch JD, et al. Predictors and outcomes of candiduria in renal transplant recipients. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 2005;40(10):1413-1421\n'},{id:"B101",body:'Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. The New England Journal of Medicine. 1969;280(14):735-739\n'},{id:"B102",body:'Zhang R. Donor-specific antibodies in kidney transplant recipients. Clinical Journal of the American Society of Nephrology. 2018;13(1):182-192\n'},{id:"B103",body:'Wu WK, Famure O, Li Y, Kim SJ. Delayed graft function and the risk of acute rejection in the modern era of kidney transplantation. Kidney International. 2015;88(4):851-858\n'},{id:"B104",body:'Pascual J, Berger SP, Witzke O, Tedesco H, Mulgaonkar S, Qazi Y, et al. Everolimus with reduced calcineurin inhibitor exposure in renal transplantation. Journal of the American Society of Nephrology. 2018;29(7):1979-1991\n'},{id:"B105",body:'Group CSC, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, et al. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): A randomised trial. Lancet. 2014;384(9955):1684-1690\n'},{id:"B106",body:'Tanriover B, Jaikaransingh V, MacConmara MP, Parekh JR, Levea SL, Ariyamuthu VK, et al. Acute rejection rates and graft outcomes according to induction regimen among recipients of kidneys from deceased donors treated with tacrolimus and mycophenolate. Clinical Journal of the American Society of Nephrology. 2016;11(9):1650-1661\n'},{id:"B107",body:'Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018;18(2):293-307\n'},{id:"B108",body:'Roufosse C, Simmonds N, Clahsen-van Groningen M, Haas M, Henriksen KJ, Horsfield C, et al. A 2018 reference guide to the Banff classification of renal allograft pathology. Transplantation. 2018;102(11):1795-1814\n'},{id:"B109",body:'Webster AC, Wu S, Tallapragada K, Park MY, Chapman JR, Carr SJ. Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients. The Cochrane Database of Systematic Reviews. 2017;7:Cd004756\n'},{id:"B110",body:'Lefaucheur C, Loupy A. Antibody-mediated rejection of solid-organ allografts. The New England Journal of Medicine. 2018;379(26):2580-2582\n'},{id:"B111",body:'Wan SS, Ying TD, Wyburn K, Roberts DM, Wyld M, Chadban SJ. The treatment of antibody-mediated rejection in kidney transplantation: An updated systematic review and meta-analysis. Transplantation. 2018;102(4):557-568\n'},{id:"B112",body:'Velidedeoglu E, Cavaille-Coll MW, Bala S, Belen OA, Wang Y, Albrecht R. Summary of 2017 FDA Public Workshop: Antibody-mediated rejection in kidney transplantation. Transplantation. 2018;102(6):e257-ee64\n'},{id:"B113",body:'Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M, et al. A randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. Journal of the American Society of Nephrology. 2018;29(2):591-605\n'},{id:"B114",body:'Sautenet B, Blancho G, Buchler M, Morelon E, Toupance O, Barrou B, et al. One-year results of the effects of rituximab on acute antibody-mediated rejection in renal transplantation: RITUX ERAH, a multicenter double-blind randomized placebo-controlled trial. Transplantation. 2016;100(2):391-399\n'},{id:"B115",body:'Becker YT, Becker BN, Pirsch JD, Sollinger HW. Rituximab as treatment for refractory kidney transplant rejection. American Journal of Transplantation. 2004;4(6):996-1001\n'},{id:"B116",body:'Morris PJ. Transplantation—A medical miracle of the 20th century. The New England Journal of Medicine. 2004;351(26):2678-2680\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Sebastian Hultin",address:null,affiliation:'
Department of Nephrology, Princess Alexandra Hospital, Australia
'},{corresp:null,contributorFullName:"Carmel M. Hawley",address:null,affiliation:'
Department of Nephrology, Princess Alexandra Hospital, Australia
Australasian Kidney Trials Network, Centre for Health Services Research, University of Queensland, Australia
Translational Research Unit, Australia
'},{corresp:null,contributorFullName:"David W. Johnson",address:null,affiliation:'
Department of Nephrology, Princess Alexandra Hospital, Australia
Australasian Kidney Trials Network, Centre for Health Services Research, University of Queensland, Australia
Translational Research Unit, Australia
'},{corresp:"yes",contributorFullName:"Ross S. Francis",address:"ross.francis@health.qld.gov.au",affiliation:'
Department of Nephrology, Princess Alexandra Hospital, Australia
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1. Introduction
Melatonin (N-acetyl-5-methoxy-tryptamine) is a hormone taking place in many biological and physiological processes and is a multifunctional indolamine compound synthesized mainly from the metabolism of tryptophan via serotonin in the pineal gland [1]. Its molecular formula is C13H16N2O2 and its molecular weight is 232.278 g/mol (Figure 1) [2]. It has the capacity to be able to pass through all biological membranes due to its small molecular size and high lipophilicity and it is evenly distributed to all biological tissues and fluids by crossing the blood–brain barrier [3].
Figure 1.
Chemical structure of melatonin.
Although the existence of the pineal gland has been known since ancient times, the French philosopher Rene Descartes described the pineal gland as the “throne of the soul” about three hundred years ago [4]. Melatonin hormone was first described in 1958 by the American dermatologist Aaron Lerner by obtaining from the pineal gland of cattle [5]. Melatonin, which is produced in the cells called pinealocytes of the pineal gland, is a hormone that plays a role in the regulation of many physiological and biological functions, such as circadian rhythm, sleep/wake cycle, pubertal development-reproduction, locomotor activity, regulation of immunity and blood pressure, molting, and hibernation [6, 7, 8, 9, 10].
Cortisol and melatonin levels act in opposite directions. Immediately after cortisol levels drop at night, melatonin levels begin to increase. The balance between these two hormones is important for good health and various diseases can occur with low melatonin and high cortisol levels [11, 12].
While melatonin shows a stimulating effect on the gonads in animals, such as sheep, goats, and deer, it shows suppressive properties in animals, such as horses, hamsters, and camels [13]. Melatonin acts as a timer by providing to follow-up the changes in the light/dark ratio of the animal seasonally [14].
In sheep, melatonin secretion and plasma levels are low in daylight [15, 16]. After sunset, melatonin secretion increases 10–20 times and rises rapidly to reach a peak by the end of the night. Thus, melatonin signal reflects the duration of the dark phase [14]. Melatonin initiates a series of events that lead to the start of the reproduction season [17]. The decreasing light exposure time increases melatonin secretion in the autumn-winter months when the days start to get shorter. Increased melatonin secretion stimulates gonadotrophin-releasing hormone (GnRH) secretion and provides to initiate estrus by acting on the hypothalamus in sheep [18, 19].
2. Melatonin
2.1 Tryptophan synthesis
The shikimate pathway is found in bacteria, fungi, plants, and algae, as well as in some protozoans. However, this pathway does not occur in animals and therefore animals must obtain aromatic amino acids from their diets as essential nutrients. Phosphoenolpyruvate (PEP), sugar with 3-carbon, product of the glycolysis pathway and erythrose-4-phosphate (E4-P), sugar with 4-carbon, synthesized from the pentose phosphate pathway starts with its conversion to 2-keto-3-deoxy-D-arabinoheptulosonate 7-phosphate, 7-carbon compound, with the hydrolysis of phosphate by 2-keto-3-deoxy-D-arabino-heptulosonate 7-phosphate synthase enzyme [20, 21].
In the second reaction, 3-dehydroquinate, a cyclic product, occurs by elimination of phosphate from 2-keto-3-deoxy-D-arabinoheptulosonate 7-phosphate by the catalysis of 3-dehydroquinate synthase enzyme with the help of NAD+. 3-dehydroshikimate is formed from this product with the effect of 3-dehydroquinate dehydratase enzyme as a result of the loss of the H2O molecule [20, 22].
The next reaction is the reduction of 3-dehydroshikimate to shikimate by the shikimate dehydrogenase enzyme, which is used as a cofactor with NADPH. It is converted to shikimate 3-phosphate by the shikimate kinase enzyme by using one ATP per molecule. 5-enolpyruvylshikimate-3-phosphate is formed from shikimate 3-phosphate by binding to phosphoenolpyruvate (PEP) and catalyzing with 5-enolpyruvylshikimate-3-phosphate synthase enzyme. In the last reaction, 5-enolpyruvylshikimate-3-phosphate is converted to chorismate by the enzyme chorismate synthase [21, 23].
It forms anthranilate from chorismate formed in the last reaction of the shikimate pathway by giving amino group, which is part of the indole ring, in subsequent reactions for glutamine amino acid by way of the anthranilate synthase enzyme, which catalyzes the initial reaction of tryptophan biosynthesis [22]. N-(5′-phosphoribosyl) anthranilate is formed as a result of the elimination of pyrophosphate from phosphoribosyl-pyrophosphate (PRPP) by the enzyme anthranilate phosphoribosyltransferase. N-(5′-phosphoribosyl) anthranilate isomerase is responsible for the isomerization of N-(5′-phosphoribosyl) anthranilate to enol-1-o-carboxyphenylamino-1-deoxy-ribulose phosphate [24, 25].
Indole-3-glycerol-phosphate synthase catalyzes its conversion to indole-3-glycerol-phosphate by decarboxylating enol-1-o-carboxyphenylamino-1-deoxy-ribulose phosphate. In the last reaction, tryptophan synthase catalyzes the formation of tryptophan from indole-3-glycerol-phosphate by using indole and serine amino acids (Figure 2) [21, 26].
Figure 2.
Tryptophan synthesis.
2.2 Synthesis of melatonin
Anabolism: Tryptophan is a nonpolar amino acid containing an indole ring [27]. Tryptophan amino acid, which is in the class of essential amino acids, is required to be taken from the diet through nutrition since it cannot be synthesized in humans and monogastric animals [20].
Melatonin, which is synthesized from the amino acid tryptophan, is synthesized in bacteria, unicellular eukaryotes, and plants. Melatonin is synthesized from retina, gastrointestinal system, kidney, liver, thyroid gland, bone marrow, leukocytes, membranous cochlea, placenta, Harderian gland, gonads, breast tissue, adrenal gland, lung, skin, adipose tissue, blood vessels, lymphocytes, neutrophils, lymphoid tissues, and some brain areas, is mainly synthesized from the pineal gland [28, 29].
The pineal gland plays an important role as a functional neuroendocrine transducer of photoperiodic changes that occur in environmental or seasonal events by activating N-acetyl transferase transfer [30]. Norepinephrine is the most important transmitter in the postganglionic sympathetic nerve endings in this gland. The suprachiasmatic nucleus (SCN), which is one of the nuclei that can receive signals from the retina through nerves during the day and in light, effectively inhibits the release of norepinephrine from these nerve endings [31, 32]. In the dark, the release of norepinephrine from the nerve endings begins. Norepinephrine then binds to β-adrenergic receptors on the pinealocyte membrane and causes an increase in intracellular cAMP. As a result, it increases the activity of the N-acetyltransferase enzyme, which is a rate-limiting enzyme in melatonin synthesis in increasing intracellular cAMP and melatonin synthesis increases from serotonin [32, 30].
Melatonin synthesis begins with the uptake of tryptophan from the circulatory system by pinealocytes [33]. While tryptophan is converted to 5-hydroxy-tryptophan by the tryptophan hydroxylase enzyme catalysis, 5-hydroxy-tryptophan is also converted to serotonin (5-hydroxy-tryptamine) via aromatic L-amino acid decarboxylase [34]. N-acetyl serotonin is formed with the catalysis of 5-hydroxy-tryptamine N-acetyltransferase enzyme. N-acetyl serotonin is converted into melatonin (N-acetyl-5-methoxy-tryptamine) by being methylated with the catalysis of 5-hydroxyindole-o-methyltransferase enzyme (Figure 3) [28, 35, 36].
Figure 3.
Anabolism and catabolism of melatonin.
Catabolism: Melatonin is metabolized by isoforms of cytochrome P450 mono-oxygenase enzymes (CYP1A2, CYP1A1, and CYP1B1) found in the liver. Of these isoforms, both CYP1A2 and CY2C19 enzymes can demethylate melatonin to N-acetyl serotonin or can convert melatonin to 6-hydroxymelatonin by hydroxylation [37]. The half-life of melatonin, of which 70% is transported to the liver depending on albumin, varies between 3 and 45 minutes [38]. Less than 1% of melatonin is reported to be excreted with urine as 6-sulphatoxymelatonin by conjugating lesser extent with glucuronic acid or mostly conjugating with sulfate for the rest (Figure 3) [39, 40].
3. Antioxidant effects of melatonin
Free radicals, which are low molecular weight, short-lived and unstable structures, are highly active chemical structures that have unpaired electrons in their final orbits and try to share the electrons of other compounds to make up for this gap [41, 42]. Free radicals, which cause oxidation, are mainly oxygen-derived metabolites, superoxide anions (O2−), hydrogen peroxide (H2O2), hydroxyl radical (OH−), and lipid peroxides [43]. Oxidative stress occurs as a result of increased reactive oxygen species (ROS) for various reasons and insufficient antioxidant mechanisms. Free radicals, which are formed by natural metabolic pathways in the body, are normally eliminated by radical scavenging antioxidant systems. Antioxidants are the molecules that prevent cell damage by inhibiting the formation of free radicals or scavenging existing radicals [44, 45]. While antioxidants can be classified according to their structure as those being enzymatic [superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and glutathione-S-transferase (GST)] and non-enzymatic [Reduced glutathione (GSH), vitamin A, vitamin C, vitamin E, and melatonin], they can also be classified according to their cell localization as (i) intracellular antioxidants (SOD, CAT, and GPx), (ii) extracellular antioxidants (albumin, vitamin C, and urate) and (iii) membrane antioxidants (vitamin A and vitamin E) [46].
Melatonin hormone, which is a non-enzyme antioxidant, helps to eliminate harmful conditions stimulated by oxidative stress by inhibiting protein oxidation, lipid peroxidation, mitochondrial damage, and DNA degradation due to both its direct free radical scavenging activity and its contribution to the antioxidant defense system [47]. Melatonin, which is an antioxidant and was first suggested in 1991 by Ianaş et al., keeps radicals before the membrane and detoxifies them by protecting the membrane by attaching them to the outer surface of the cell membrane [48]. Melatonin hormone removes hydroxyl and oxygen radicals and inhibits nitric oxide synthase [49] and this feature of melatonin [50] that prevents lipid peroxidation reactions, especially by scavenging the OH˙ radical, is due to the pyrrole ring in its structure [51]. Melatonin increases the levels of antioxidant enzymes, such as mitochondrial SOD, cytosolic SOD, GPx, and GSH in the cell [52]. In addition, it is a powerful antioxidant that prevents oxidative and nitrosative damage due to its ability to eliminate toxic oxygen derivatives formed in metabolic activities and reduces the formation of ROS and reactive nitrogen species [32, 53].
Melatonin shows its antioxidant effect in three ways. (i) Direct antioxidant effect: Blocking free radicals with the formation of N1-Acetyl-N2-formyl-5-methoxyquinuramine from the pyrrole ring of melatonin in the presence of free radicals [54, 55, 56, 57], (ii) Indirect antioxidant effect: Suppressing oxidative stress by increasing the activity of enzymes, such as SOD, GPx, and GSH [54, 55], and (iii) Effect via prooxidant enzyme: Reducing free radical formation as a result of suppressing some prooxidant enzymes [48].
Antioxidant properties of melatonin have been shown in the studies conducted [58, 59, 60, 61, 62]. It has been reported that melatonin is at least two times more effective antioxidant than vitamin E and five times more effective than glutathione [55]. In the studies conducted, it is known that when melatonin is applied together with vitamin E and vitamin C, better protection is obtained than when applied alone [63] and melatonin has a suppressive effect on the formation of free radicals formed during electron transport in mitochondria. Melatonin reduces the formation of destructive toxic hydroxyl radicals by chelating transition metals taking place in Fenton/Haber-Weiss reactions [64]. It protects the biomolecules found in the whole structure of the cell against free radical formation by reacting with toxic hydroxyl radicals. Melatonin forms a non-enzymatic defense mechanism against the destructive properties of hydroxyl radicals and is more effective than other known antioxidants in protecting the organism against oxidative damage. It terminates lipid peroxidation by capturing the peroxide radical unlike antioxidants, such as ascorbic acid, alpha-tocopherol, and GSH. It has been reported that liver, kidney, and brain tissue glutathione peroxidase activity in rats increased after the administration of melatonin. Significant decreases in liver, lung, brain tissue, and glutathione peroxidase activity were reported in rats for which pinealectomy is made [48].
Many studies examining the effects on the synthesis and circulating amount of nitric oxide (NO), which is an important molecule of melatonin that plays a role in many physiological and physiopathological events, have been done. The physiological effect of NO occurs when soluble guanylate cyclase is activated to form cGMP. Decreased melatonin level causes decreased guanylate cyclase activity in many tissues. As a result, the cGMP level decreases, and the cAMP level increases. Thus, cell membrane thickness and rigidity increase, and degenerative damage formation accelerates [65]. When the relationship between NO and melatonin is examined, it has been suggested that the peroxynitrite anion, which is formed as a result of the reaction between NO and nitrosomelatonin and the reaction of NO and O2 in the presence of O2, is also occupied by melatonin [66, 67].
Unlike other antioxidants, it does not have a toxic effect in excessive use. Melatonin differs from classical antioxidants in various aspects and turns into less harmful pro-oxidant substances from the oxidants whose effects they abolish. However, after melatonin effects oxidant substances, is also effective as antioxidants in the intermediate stages and the resulting products. This property is very valuable as an antioxidant agent and is characterized as a “suicidal or terminal antioxidant” [68]. Melatonin reduces the synthesis of adhesion molecules and proinflammatory cytokines [69, 70]. Melatonin prevents linoleic acid, which is an energy source and growth factor of melatonin, which promotes the repair of damaged DNA, from entering the cell and suppresses its metabolism [71, 72].
4. Conclusion
The shikimate pathway, used by bacteria, fungi, algae, and plants, is a seven-step metabolic pathway for the biosynthesis of aromatic amino acids. However, this pathway is absent in animals. For this reason, melatonin, a neurohormone synthesized from tryptophan, an essential amino acid that must be taken with food, is synthesized by the retina, bone marrow, and gastrointestinal system, mainly by the pineal gland. Melatonin plays a role in the regulation of many physiological and biological functions in animals, such as the regulation of sleep time, blood pressure, and breeding season. In addition, due to its small molecular size and high lipophilic, it can reach all organelles of the cell and cross the blood–brain barrier. In addition, melatonin, which is a powerful antioxidant, provides direct scavenging of hydroxyl and oxygen radicals with high toxicity and stimulates antioxidant enzymes.
\n',keywords:"antioxidant, biochemistry, melatonin, shikimate pathway, tryptophan",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/82790.pdf",chapterXML:"https://mts.intechopen.com/source/xml/82790.xml",downloadPdfUrl:"/chapter/pdf-download/82790",previewPdfUrl:"/chapter/pdf-preview/82790",totalDownloads:32,totalViews:0,totalCrossrefCites:0,dateSubmitted:"June 29th 2022",dateReviewed:"July 4th 2022",datePrePublished:"July 29th 2022",datePublished:null,dateFinished:"July 23rd 2022",readingETA:"0",abstract:"Melatonin (N-acetyl-5-methoxy-tryptamine) is a hormone taking place in many biological and physiological processes, such as reproduction, sleep, antioxidant effect, and circadian rhythm (biological clock), and is a multifunctional indolamine compound synthesized mainly from the metabolism of tryptophan via serotonin in the pineal gland. Melatonin, which is a hormone synthesized from the essential amino acid tryptophan, is substantially secreted from the pineal gland between the cerebral hemispheres found in the mammalian brain. In addition to this, it is also produced in the cells and tissues, such as the gastrointestinal system, gall, epithelial hair follicles, skin, retina, spleen, testis, salivary glands, bone marrow, leukocytes, placenta, and thrombocytes. It plays a role in many physiological events, such as synchronizing circadian rhythms, reproduction, fattening, molting, hibernation, and change of pigment granules, preserving the integrity of the gastrointestinal system with an anti-ulcerative effect in tissues and organs from which it is produced. Melatonin is also a powerful antioxidant and anti-apoptotic agent that prevents oxidative and nitrosative damage to all macromolecules due to its ability to form in metabolic activities, directly excrete toxic oxygen derivatives, and reduce the formation of reactive oxygen and nitrogen species. In this book chapter, we will explain the structure, synthesis, metabolism, and antioxidant effects of the melatonin hormone.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/82790",risUrl:"/chapter/ris/82790",signatures:"Oguz Merhan",book:{id:"11707",type:"book",title:"Melatonin - Recent Updates",subtitle:null,fullTitle:"Melatonin - Recent Updates",slug:null,publishedDate:null,bookSignature:"Dr. Volkan Gelen, Dr. Emin Şengül and Dr. Abdulsamed Kükürt",coverURL:"https://cdn.intechopen.com/books/images_new/11707.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80356-735-8",printIsbn:"978-1-80356-734-1",pdfIsbn:"978-1-80356-736-5",isAvailableForWebshopOrdering:!0,editors:[{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"192516",title:"Associate Prof.",name:"Oguz",middleName:null,surname:"Merhan",fullName:"Oguz Merhan",slug:"oguz-merhan",email:"oguzmerhan@hotmail.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192516/images/5635_n.jpg",institution:{name:"Kafkas University",institutionURL:null,country:{name:"Turkey"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Melatonin",level:"1"},{id:"sec_2_2",title:"2.1 Tryptophan synthesis",level:"2"},{id:"sec_3_2",title:"2.2 Synthesis of melatonin",level:"2"},{id:"sec_5",title:"3. Antioxidant effects of melatonin",level:"1"},{id:"sec_6",title:"4. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Molaakbari E, Mostafavi A, Beitollahi H. Simultaneous electrochemical determination of dopamine, melatonin, methionine and caffeine. Sensors and Actuators B: Chemical. 2015;208:195-203. DOI: 10.1016/j.snb.2014.10.130'},{id:"B2",body:'Sun R, Wang Y, He H, Wan Y, Li L, Sha J, et al. Solubility measurement, solubility behavior analysis and thermodynamic modelling of melatonin in twelve pure solvents from 278.15 K to 323.15 K. Journal of Molecular Liquids. 2020;319:114139'},{id:"B3",body:'Babaei A, Taheri AR, Farahani IK. 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Molecular targets for the management of gastrointestinal cancer using melatonin, a natural endogenous body hormone. Biomedicine and Pharmacotherapy. 2021;140:111782. DOI: 10.1016/j.biopha.2021.111782'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Oguz Merhan",address:"oguzmerhan@hotmail.com",affiliation:'
Faculty of Veterinary, Department of Biochemistry, Kafkas University, Kars, Turkey
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He was born in 1964 at Kendadji, Tillabéri, Niger. He got his first degree in Agricultural Sciences from the Abdou Moumouni University and later specialised in Arid Regions Forestry (ENGREF, Montpellier, France). He pursued his studies at the University of Ouagadougou, Burkina Faso where he obtained his M. Phil in 1997. In 2000, he got a tenure appointment at the Faculty of Sciences at Abdou Moumouni University. He registered for his Ph. D thesis at the Université Libre de Bruxelles, Belgium in April 2005. He published more than 38 Scientifics articles both in national and international journals. 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Singh",profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"8018",title:"Extracellular Matrix",subtitle:"Developments and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/8018.jpg",slug:"extracellular-matrix-developments-and-therapeutics",publishedDate:"October 27th 2021",editedByType:"Edited by",bookSignature:"Rama Sashank Madhurapantula, Joseph Orgel P.R.O. and Zvi Loewy",hash:"c85e82851e80b40282ff9be99ddf2046",volumeInSeries:23,fullTitle:"Extracellular Matrix - Developments and Therapeutics",editors:[{id:"212416",title:"Dr.",name:"Rama Sashank",middleName:null,surname:"Madhurapantula",slug:"rama-sashank-madhurapantula",fullName:"Rama Sashank Madhurapantula",profilePictureURL:"https://mts.intechopen.com/storage/users/212416/images/system/212416.jpg",institutionString:"Illinois Institute of Technology",institution:{name:"Illinois Institute of Technology",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Proteomics",value:18,count:4},{group:"subseries",caption:"Metabolism",value:17,count:6},{group:"subseries",caption:"Cell and Molecular Biology",value:14,count:9},{group:"subseries",caption:"Chemical Biology",value:15,count:14}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:9},{group:"publicationYear",caption:"2021",value:2021,count:7},{group:"publicationYear",caption:"2020",value:2020,count:12},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:2}],authors:{paginationCount:148,paginationItems:[{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",biography:"Vahid Asadpour, MS, Ph.D., is currently with the Department of Research and Evaluation, Kaiser Permanente Southern California. He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. 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\r\n\tThe era of antibiotics led us to the illusion that the problem of bacterial infection is over. However, bacterial flexibility and adaptation mechanisms allow them to survive and grow in extreme conditions. The best example is the formation of a sophisticated society of bacteria defined as a biofilm. Understanding the mechanism of bacterial biofilm formation has changed our perception of the development of bacterial infection but successfully eradicating biofilm remains a challenge. Considering the above, it is not surprising that bacteria remain a major public health threat despite the development of many groups of antibiotics. Additionally, increasing prevalence of acquired antibiotic resistance forces us to realize that we are far from controlling the development of bacterial infections. On the other hand, many infections are endogenous and result from an unbalanced relationship between the host and the microorganism. The increasing use of immunosuppressants, such as chemotherapy or organ transplantation, increases the incidence of patients highly susceptible to bacterial infections in the population.
\r\n
\r\n\tThis topic will focus on the current challenges and advantages in the diagnosis and treatment of bacterial infections. We will discuss the host-microbiota relationship, the treatment of chronic infections due to biofilm formation, and the development of new diagnostic tools to rapidly distinguish between colonization and probable infection.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",keywords:"Antibiotics, Biofilm, Antibiotic Resistance, Host-microbiota Relationship, Treatment, Diagnostic Tools"},{id:"4",title:"Fungal Infectious Diseases",scope:"Fungi are ubiquitous and there are almost no non-pathogenic fungi. Fungal infectious illness prevalence and prognosis are determined by the exposure between fungi and host, host immunological state, fungal virulence, and early and accurate diagnosis and treatment. \r\nPatients with both congenital and acquired immunodeficiency are more likely to be infected with opportunistic mycosis. Fungal infectious disease outbreaks are common during the post- disaster rebuilding era, which is characterised by high population density, migration, and poor health and medical conditions.\r\nSystemic or local fungal infection is mainly associated with the fungi directly inhaled or inoculated in the environment during the disaster. The most common fungal infection pathways are human to human (anthropophilic), animal to human (zoophilic), and environment to human (soilophile). Diseases are common as a result of widespread exposure to pathogenic fungus dispersed into the environment. \r\nFungi that are both common and emerging are intertwined. In Southeast Asia, for example, Talaromyces marneffei is an important pathogenic thermally dimorphic fungus that causes systemic mycosis. Widespread fungal infections with complicated and variable clinical manifestations, such as Candida auris infection resistant to several antifungal medicines, Covid-19 associated with Trichoderma, and terbinafine resistant dermatophytosis in India, are among the most serious disorders. \r\nInappropriate local or systemic use of glucocorticoids, as well as their immunosuppressive effects, may lead to changes in fungal infection spectrum and clinical characteristics. Hematogenous candidiasis is a worrisome issue that affects people all over the world, particularly ICU patients. CARD9 deficiency and fungal infection have been major issues in recent years. Invasive aspergillosis is associated with a significant death rate. Special attention should be given to endemic fungal infections, identification of important clinical fungal infections advanced in yeasts, filamentous fungal infections, skin mycobiome and fungal genomes, and immunity to fungal infections.\r\nIn addition, endemic fungal diseases or uncommon fungal infections caused by Mucor irregularis, dermatophytosis, Malassezia, cryptococcosis, chromoblastomycosis, coccidiosis, blastomycosis, histoplasmosis, sporotrichosis, and other fungi, should be monitored. \r\nThis topic includes the research progress on the etiology and pathogenesis of fungal infections, new methods of isolation and identification, rapid detection, drug sensitivity testing, new antifungal drugs, schemes and case series reports. It will provide significant opportunities and support for scientists, clinical doctors, mycologists, antifungal drug researchers, public health practitioners, and epidemiologists from all over the world to share new research, ideas and solutions to promote the development and progress of medical mycology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",keywords:"Emerging Fungal Pathogens, Invasive Infections, Epidemiology, Cell Membrane, Fungal Virulence, Diagnosis, Treatment"},{id:"5",title:"Parasitic Infectious Diseases",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology"},{id:"6",title:"Viral Infectious Diseases",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. This series will focus on various crucial factors related to emerging viral infectious diseases, including epidemiology, pathogenesis, host immune response, clinical manifestations, diagnosis, treatment, and clinical recommendations for managing viral infectious diseases, highlighting the recent issues with future directions for effective therapeutic strategies.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",keywords:"Novel Viruses, Virus Transmission, Virus Evolution, Molecular Virology, Control and Prevention, Virus-host Interaction"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/113228",hash:"",query:{},params:{id:"113228"},fullPath:"/profiles/113228",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()