Most frequently found Candida species in human disease.
\r\n\t
",isbn:"978-1-83968-388-6",printIsbn:"978-1-83968-387-9",pdfIsbn:"978-1-83968-389-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"61ec2bad4fc3f7060fd64b91fa12e82c",bookSignature:"Ph.D. Vicente Vanaclocha",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10574.jpg",keywords:"Prevalence, Incidence, Worldwide Differences, Red Flags, Moyamoya and School Performance, Medical Treatment, Surgical Treatment, Genetic Markers, Immunologic Factors, Recommended Anesthetic Agents, Source of Intraoperative Complications, Post-Operative ICU Management",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 23rd 2020",dateEndSecondStepPublish:"October 21st 2020",dateEndThirdStepPublish:"December 20th 2020",dateEndFourthStepPublish:"March 10th 2021",dateEndFifthStepPublish:"May 9th 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Vicente Vanaclocha is a Chief of Neurosurgery at the University Hospital of Navarra and head of Neurosurgery Service of San Jaime Hospital in Torrevieja. He has over 25 years of experience in neuro-oncology and minimally invasive surgery techniques. He is a pioneer in many areas in neurosurgery (treatment of brain tumors, Chiari Malformation, and sacroiliac joint disorders).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"199099",title:"Ph.D.",name:"Vicente",middleName:null,surname:"Vanaclocha",slug:"vicente-vanaclocha",fullName:"Vicente Vanaclocha",profilePictureURL:"https://mts.intechopen.com/storage/users/199099/images/system/199099.jpeg",biography:"Vicente Vanaclocha is Chief of Neurosurgery. Doctor of Medicine from the University of Valencia, he has over 25 years experience in neuro-oncology, minimally invasive and minimally invasive surgery techniques. Specialist in neurosurgery both nationally and internationally (including the General Medical Register of England and stay at the Groote Schuur Hospital in Cape Town, South Africa) has been Chief of Neurosurgery at the University Hospital of Navarra and head of Neurosurgery Service of San Jaime Hospital in Torrevieja. He was also associate professor of neurosurgery at the Faculty of Medicine of the University of Navarra and is a professor of neuroanatomy at the Catholic University of Valencia also serving as an editorial board member of repute.\nCurrently he is Associate Professor at the University of Valencia.",institutionString:"University of Valencia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"7",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Valencia",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"19063",title:"Surgical Complications of Renal Transplantation",doi:"10.5772/16767",slug:"surgical-complications-of-renal-transplantation",body:'\n\t\tIn the early era of kidney transplant, surgical complications were a major cause of graft loss. Between 1960 and 1980, the estimated incidence was around 20%. With the improvement of surgical techniques, the frequency of these complications has dropped significantly and this subject until then common in the medical literature came to be seldom discussed (Botto V, 1993; Hernandez D, 2006). Currently, it is estimated that in large transplant centers the incidence of surgical complications is less than 5%. In general, the results of renal transplantation have improved primarily as a consequence of advances in medical and immunosuppressive therapy and progress in surgical techniques. Posttransplant urologic complications are unusual, with the range of 2.5% to 27% in most series, and can cause significant morbidity and mortality (Zargar MA, 2005; Dalgic A, 2006) Results have improved over the past decade as a direct application of less invasive endourologic diagnostic and therapeutic techniques of the surgical complications (Streem SS, 1994).
\n\t\t\tHowever, the etiologies are the most common technical problems and association with immunological complications. Surgical complications after renal transplantation can be classified mainly as vascular (arterial and venous thrombosis, renal arterial stenosis, lymphocele, hemorrhage) and urologic (ureteral obstruction, vesicoureteral reflux, urinary fistula), although other types of complications are not uncommon, like graft’s rupture and hematoma. These complications can occur early in the intra-operative, immediate postoperative period or later, and imply in increase morbidity, hospitalization and costs (Humar A, 2005).
\n\t\t\tUrologic complications are the most common surgical complication after renal transplantation, causing significant morbidity and mortality. Recently, the incidence of urologic complications after renal transplantation has decreased to 2.5% to 12.5% (Emiroglu R, 2001). Unfortunately, there is a still higher incidence of technical complications in pediatric recipients, reaching approximately 20% with an associated 58% and 74% graft survival rates for cadaveric and living-related transplantation (Salvatierra O Jr, 1997; US Renal Data System, 1996). Urologic complications represent an important cause of morbidity, delaying normal graft functioning, and in some cases leading graft loss and/or patient death (Beyga ZT, 1998; Colfry AJ Jr, 1974; Mundy AR, 1981; Hakim NS, 1994).
\n\t\t\tThe most frequent urological complications after kidney transplantation involves the ureterovesical anastomosis (fistula, stenosis and reflux), with a frequency ranging from 5% to 10% in different séries.
\n\t\tThis is the leakage of urine from the collecting system. It can occur at the level of the bladder, ureter or renal calices. The leakage of urine can be collected around the graft, move to the retroperitoneum, scrotum or may manifest through the incision. His average prevalence in many studies is around 5.7%. In general, most urinary leaks are the results of ureteral problems, failure of ureterovesical anastomosis or ischemia and necrosis of the distal ureteral stump.
\n\t\t\t\tLike the majority of surgeons now employ an extravesical ureteroneocystostomy technique for implantation of the ureter, there are shorter ureter and decreased likelihood of ischemia, and a limited cystostomy that rarely leads to leakage from the bladder (Gibbins WS, 1992; Thrasher JB, 1990).
\n\t\t\t\t\n\t\t\t\t\tClinical presentation:\n\t\t\t\t
\n\t\t\t\tIn most cases, there is constant discharge of clear liquid (yellow citrus) through the drain, in the immediate postoperative period, and sometimes the flow through the drain can even surpass the diuresis the urinary catheter.
\n\t\t\t\tWhen later, after removal of the tubular drain, there may be bulging store kidney with extension into the perineum and scrotum or decreased urine output with maintenance of renal function. Unexplained graft dysfunction, pelvic fluid collection, fever, graft tenderness, an lower extremity edema can also occur (Streen SB, 1994).
\n\t\t\t\tEarly urinary leaks can be divided into two types: the first usually occurs within the first 1 to 4 days and is almost always related to technical problems with the implantation. In this case, the ureter has usually pulled out of a tunnel caused by excessive tension at the anastomosis. This complication appears to be more common with the extravesical ureteroneocystostomies (Streen SB, 1994). Some authors have recommended use of a ureteral stent to lessen the likelihood of this complication (Gibbins WS, 1992). The second type of early ureteral leak, usually presents between 5 and 10 days, is associated with distal ureteral ischemia, which may be a consequence of injury during the donor nephectomy, technical causes such as tunnel hematoma or distal stripping of the blood supply (Rosenthal JT, 1994).
\n\t\t\t\t\n\t\t\t\t\tDiagnosis:\n\t\t\t\t
\n\t\t\t\tFor being the most common surgical complication of kidney transplantation, urinary fistula is easily diagnosed. In doubtful cases, where there is need to exclude the lymphocele as main differential diagnosis, biochemical analysis of the liquid is characterized by having elevated levels of creatinine, urea and potassium. In the lymphocele, creatinine should be similar of blood. Urinary leak are often suspected because of increased drainage from the wound. Radiographic tests of help include an abdominal ultrasound and nuclear renal scan. The ultrasound is nonspecific for evaluating patients with suspected urinary fistula after kidney transplantation. It will only reveal a fluid collection (anechoic image) around the graft. A renal scan demonstrating extravasation (figures 1, 2) is the most sensitive method to differentiate a urine leak from other fluid collections such lymphoceles or hematomas (Bretan PN Jr, 1989). A cystogram should be performed if a bladder leak is suspected.
\n\t\t\t\tRenal scan with contrast early extravasation (urinary fistula).
Late renal scan without contrast extravasation (no fistula).
In the evaluation of transplant patients, nuclear medicine can contribute in the earliest complications that may arise in the period immediately following transplantation, as in the late complications and complications of surgical nature. A landmark study, conducted an initial assessment within the first 72 hours of surgery, is important so that we can better assess possible changes in the course of evolution. Studies with DTPA or MAG3 are the ones who will advise on the vascular phase and functional phase, and excretory phase, all parameters of the utmost importance in the evaluation of the graft (Kahan BD, 1989; Luk SH, 1999).
\n\t\t\t\tAs surgical complications of kidney transplantation, the urinary fistulas are observed by scintigraphy an accumulation of the radiotracer outside the kidney (Luk SH, 1999). In cases of hematoma, other surgical complication, shows an area of low concentration of the tracer near the kidney, which may cause displacement of large structures such as vessels, ureter, bladder and collecting system obstruction. The diuretic renogram may help elucidate this issue, because the transplanted kidney has the same performance as a native kidney scintigraphy.
\n\t\t\t\t\n\t\t\t\t\tManagement of the urinary fistula:\n\t\t\t\t
\n\t\t\t\tDisruption of urinary tract in a renal transplant patient or graft dysfunction requires rapid diagnosis and treatment. Ureteral leakage needs careful and accurate diagnosis of the exact cause and site. It is important to know if the problem has a physical cause such a leak or an obstruction and is not associated with an acute rejection episode that required specific treatment (Streen SB, 1994; Rosenthal JT, 1994).
\n\t\t\t\tSurgical treatment has to be performed in all patients except those presenting with minimal extravasation at the ureteral reimplantation site and clinically stable. This group was initially treated by urinary drainage. In cases of unfavorable outcome after clinical treatment, surgery is indicated. Surgery is the initial aproach for big extravasation or when leaks arising from the mid or upper ureter were suspected. We use the same incision of the transplant to access the fistulae. The type of surgical reconstruction is based on the intraoperative evaluation of the extent of the ureteral necrosis and local and systemic condition of the patient at the time of surgery. Primary reconstruction with the ureter of the recipient or a new ureteral reimplantation are performed preferentially when local and systemic condition allowed; if local or systemic infection are present and the patient is clinically unstable an ureteral ligature associated to a nephrostomy can be performed. Ureteral stenting alone is used exceptionally. All patients received prophylactic or therapeutic antibiotic according to the antibiogram of the collected fluid (Mazzucchi E, 2006).
\n\t\t\t\tThe need for immediate open operative surgical intervention has been replaced, to a large extent, by early endourologic intervention (Banowsky LHW, 1991). The placement of a percutaneous nephrostomy can divert a leak or relieve obstruction and allow more definitive diagnosis. As described by Streem et al., endourologic management can select patients for whom the likelihood of successful nonoperative management is good. In a few cases, percutaneous access can offer long-term treatment with chronic stent management. Percutaneous techniques like nephrostomy associated to antegrade ureteral stenting works in 40% of a much selected group of patients presenting with small fistulae from the distal ureter (Campbell SC, 1993).
\n\t\t\t\tEarly open surgery is our preferred approach. Our policy is to perform primary urinary tract reconstruction whenever local and systemic condition allows. Termino-lateral anastomosis of the graft ureter or pelvis with the ureter of the recipient can be used as technique for the correction of urinary leaks. Some groups use termino-terminal anastomosis with the ureter of the recipient (Salomon L, 1999) with good results but can results in ureterohydronephrosis of the native kidney after ureter ligation for reconstruction. Ureteroneocystostomy “de novo” is used for reimplantation defects or for small distal ureteral necrosis and can fail in many cases due to necrosis extension or incomplete ureteral and bladder wall resection during surgery. Ureteral reimplantation remains an important option for urinary fistulae management. Ureteral ligature and nephrostomy is performed when there is gross infection of the fossa or when the patient presents in sepsis. There is also described, in cases of infected urinary fistulas and to prevent distal ureteral ligature and nephrostomy, the introduction of a Foley’s catheter throught the bladder wall. The catheter’s balloon is inflated at the transplanted renal pelvis to occlude the pyeloureteral junction and dry the region of the fistula (Suaid HJ, 2010).
\n\t\t\t\tRecurrences are due to insufficient ureter resection, leaving an ischemic stump extension of the process after the surgery or inadequate anastomosis. We recommend always leaving a double J stent in these cases in order to reduce recurrences but stents do not work if the necrosis extends. Recurrences were always managed surgically and an anastomosis with the ureter of the recipient was the first choice. Some patients can need a third procedure due to a new recurrence showing that the necrosis can extend after surgery and that extensive resection of the ureter is frequently necessary.
\n\t\t\t\tMortality directly related to the fistula or to its correction was high in the early transplantation era (Dreikom K, 1992) and nowadays is reported to range from 0 to 8% (Salomon L, 1999). These better results are due to an earlier and more aggressive approach, reduction in the amount of corticosteroids in the immunosuppressive regimen and to better antibiotics and clinical support. The increase in the experience with these cases can still improve such results.
\n\t\t\t\tRoutine ureteral stenting, to avoid urinary fistula, does not reduce significantly your incidence and its use is recommended only in special cases (contracted bladder, difficult anastomosis) (Campbell SC, 1993; Salomon L, 1999). In our center the modified Gregoir technique has been the procedure of choice in the last 35 years and the incidence of ureteral complications has been low.
\n\t\t\tUreteral obstruction and ureteral leakage are the most common urinary complication after renal transplantation (Azhar, Hassanain et al. 2010). The incidence related in literature varies from 3 to 8% (Fontana, Bertocchi et al.; Smith, Windsperger et al.; Kaskarelis, Koukoulaki et al. 2008). Obstruction may occur during the early postoperative course due to blood clots, ureteral malrotation or kinking, tight submucosal tunnel, unsuspected donor calculus (Poullain, Devevey et al. 2010) or perigraft fluid collection (Kahan and Ponticelli 2000; Campbell, Wein et al. 2007). Late ureteral obstructions generally after the first month or even at years posttransplant are secondary to chronic ischemia which leads to chronic fibrosis and strictures. Other cause includes compressive limphoceles or pelvic masses, ureteral lithiasis and rarely obstruction by ureteral carcinoma (Huurman, Baranski et al. 2008) or fungus ball (Vuruskan, Ersoy et al. 2005).
\n\t\t\t\tThe clinical presentation includes pain over the surgical site, decreased urine volume leading to oligoanuria and rise in blood pressure secondary to impaired renal function. Diagnostic tests shows gradual rise in serum creatinine. The ultrasound demonstrates pyelocaliectasis (fig. 3) or ureteropyelocaliectasis (fig. 4) in most of cases. Nuclear scintigraphy is less sensitive because the obstructed kidney also displays impaired radionuclide uptake, a sign often present in allograft rejection. When the diagnosis is unclear the antegrade pyelogram must be performed, because is an accurate method to define anatomically the site, degree of obstruction (Kahan and Ponticelli 2000).
\n\t\t\t\tThe treatment must be instituted as early as possible to avoid loss of renal graft function. Initially the nephrostomy by puncture must be done to ensure the patency of the kidney and restore renal function to normal. The definitive treatment of the obstruction is oriented according to the etiology. Stenosis ureteral at the site of bladder reimplantation is more common and can be addressed by several endourology techniques such as ureteral meatotomy or percutaneous ureteral dilation with balloon followed by angioplasty and implant of stent at the ureters. Such techniques are at acceptable levels of success especially
\n\t\t\t\tUltrasound with moderate hidronefrosis.
Ultrasound of transplant kidney with ureteroectasis secundary to distal ureteral obstruction.
when treat small lesions (Burgos, Bueno et al. 2009). However, open surgery with reconstruction of the excretory pathway is still considered the gold standard. In distal ureteral obstructions or when there is redundant ureter, we can review the ureteroneocystostomy by extravesical Lich-Gregoir modified techniques (Campos Freire, de Goes et al. 1974) or intravesical (Politano-Leadbetter, 1958).
\n\t\t\t\tWhen there are multiple, long stenosis of the ureter or even poor vascularization, it is necessary to perform the anastomosis of the renal pelvis with the host ureter (ureteropyelostomy) or the ureter with the host ureter (ureteroureterostomy). However, the last technique has a higher rate of stenosis. When the native ureters cannot be used, the “Boari flap” should be done joining the short ureteral stump or the renal donor pelvis, allowing an adequate distance to the bladder. This allows tunneling the flap under the ureter, decreasing reflux and bacterial contamination during episodes of infection at the lower urinary tract. Extreme situations may require a pyelovesicostomy with anastomosis the donor urinary pelvis directly to the bladder. In this circumstance there is direct transmission of voiding pressure to the urinary collecting system as well as any urinary infection, leading to chronic pyelonephritis and deteriorating renal graft (Kahan and Ponticelli 2000).
\n\t\t\tAlthough theoretically there is greater risk of surgical complications associated with living donors and recipients of kidneys with multiple arteries, in actuality it has not been considered more as a problem in laparoscopic (VLP) or open nephrectomy. This, indeed, is standard procedure in many transplant centers, (Wilson CH, 2005; Hsu TH, 2003) showing no significant adverse effects on the function and graft survival in VDL nephrectomies without or with hand assistance which may lead to higher vascular extension. (Saidi R, 2009; Hoda MR, 2010; Hoda MR, 2011) However, there is need for close attention to the anatomy of the donor due to the possibility of having two or more arteries and veins, or early arterial bifurcation (Benedetti E, 1995; Mazzucchi E, 2005; Harper JD, 2010). Furthermore, knowledge of microsurgical techniques for careful arterial graft reconstruction with multiple arteries and is essential for the reduction of vascular complications in these situations (Saidi R, 2009; Beckmann JH, 2008\n\t\t\t\t).
\n\t\tThe most worrisome of vascular complications, it occurs in about 1% of all kidney transplants (Penny MJ, 1994; Bakir N, 1996) arterial thrombosis can reach values lower or higher in different series (Salehipour M, 2009).
\n\t\t\tUsually results from technical difficulties in removing the organ or implant. In nephrectomy and perfusion injury may occur in the endothelial layer, facilitating the process of thrombosis. The anastomoses of small vessels or of very different sizes or twisting or bending pressure are other predisposing factors for thrombosis, making demand for assessing the floor space of the kidney as well as proper positioning of the graft at surgery. With some frequency, there is a need to adjust the length of the renal artery to avoid kinking of the same. A technical care is obliquely sectioning the end of the renal artery (espatulating), which can reduce the risk of thrombosis and stenosis. Another factor to consider is the quality of the receiver because the arterial embolization of atheromatous plaques predispose to thrombosis. Lesions in the endothelial artery caused by vascular clamp during anastomosis should also be considered (Gang S, 2009). Other situations of greater risk for vascular complications are patients receiving three or four kidney transplants, hyperacute rejection, and antiphospholipid antibodies (Gang S, 2009; Baños JLG 2005).
\n\t\t\tIn children, either as donors or as recipients, renal transplantation deserves special attention, or some authors recommend the exclusion of donors under the age of 3 years and the best use of infusion solutions to reduce vascular complications and increase survival rates graft (Irtan S, 2010).
\n\t\t\t\n\t\t\t\tClinical presentation and diagnosis:\n\t\t\t
\n\t\t\tThe hallmark of renal artery thrombosis is the absence of blood perfusion of the parenchyma, which can still be identified intra-operatively. In the postoperative period the most common clinical presentation is the sudden interruption of urinary flow, without pain in the graft. Obstruction should be excluded from the catheter by blood clots. The renal perfusion should be evaluated by DMSA renal scintigraphy, by ultrasound Doppler, and even with arteriography, if needed (Nezami N, 2007).
\n\t\t\tThe immediate surgical exploration may allow in a few cases, revascularization and recovery of the graft, especially if the diagnosis of arterial thrombosis is done before closing the incision. The loss of the graft is the most common consequence and nephrectomy should be performed (fig. 5).
\n\t\t\tNephectomy: Arterial Renal Thrombosis.
The prevalence of renal artery stenosis is around 2% to 10% (mean 3.7%) (Benoit G, 1990). Clinical picture is suggested by onset severe hypertension post-renal transplant, dysfunction or presence of acute renal failure with prolonged NTA. With a peak onset at six months, renal artery stenosis can manifest itself as early as two days and as late as two years after transplantation. Stenoses located in the line of anastomosis, especially in termino-terminal anastomosis, the most frequent etiologic factor is technical failure. Other etiologic factors are largely the same that lead to arterial thrombosis, but acting with less intensity.
\n\t\t\t\n\t\t\t\tClinical picture and diagnosis:\n\t\t\t
\n\t\t\tThe suspicion must always occur when a transplant patient started with a progressive decline of renal function, heart murmur audible (or increasing its intensity) in the graft site and hypertension refractory to medical treatment. The diagnosis may be suggested by non-invasive techniques such as ultrasound associated with (color) Doppler (sensitivity 87 to 94%, specificity 86 to 100%). Doppler ultrasound is useful as screening and may show an increased blood flow velocity > 6 kHz12 (Nezami N, 2007).
\n\t\t\tThe arteriography still remains the gold standard for diagnosis of arterial stenosis renal (Rengel M, 1998) The degree of stenosis is considered significant when more than 50% of the arterial lumen. Recently, gadolinium-enhanced MRI has allowed a noninvasive and efficacy comparable to that of renal arteriography convencional (Thornton MJ, 1999). The test with captopril, with plasma renin may be a method in the diagnosis of renal artery stenosis of kidney transplantado (Glicklich D, 1990).
\n\t\t\tThe therapy depends on the location and degree of stenosis. Conservative treatment can be used in cases of mild stenosis in which blood pressure is controlled with medication and serum creatinine level remained stable.
\n\t\t\tInvasive procedures are indicated when blood pressure is not controllable by medication, there is progressive worsening of renal function or when noninvasive tests suggest the progression of stenosis. In this situation, diagnostic arteriography is indicated in combination with transluminal angioplasty and “stenting" (fig. 6, 7) (Leertouwer TC, 2000). This technique allows restoring renal perfusion in most cases and its effectiveness is confirmed immediately by a second angiography (Ghaffari S, 2009).
\n\t\t\tIntraluminal balloon dilatation with stenting is the preferred therapy for most patients, especially recommended in cases of localized stenosis and distant > 1 cm of the anastomosis. Surgery is reserved for lesions involving the anastomosis, or the surrounding area, and in cases of early artery stenosis renal (Benoit G, 1990). Other surgical procedures are indicated when the stenosis is severe and unsuitable for angioplasty or else, in this failure. Surgical techniques include reviewing local resection of the stricture and reanastomosis, may or may not be used autologous grafts (saphenous vein) or heterologous (Teflon) in the form of a patch graft or bypass, with success rates ranging between 63 to 92% (Bruno S, 2004), (fig. 8).
\n\t\tThe renal vein thrombosis is uncommon but serious complication, with incidence ranging between 0.9 and 4.5%, usually occurring in the first week after transplantation and with great potential for graft loss (Giustacchini P, 2002). Because the transplanted kidney does not have collateral circulation, venous stasis causes impairment of blood flow and consequent loss of function.
\n\t\t\tArteriography (post-transplant) showing a renal stenosis artery.
Result after “stent” angioplasty.
Bypass iliac-renal arteries.
As causative agents related are: angulation of the renal vein or anastomotic stricture, dehydration, venous compression by lymphocele or hematoma, progression of ipsilateral iliofemoral thrombophlebitis should also be considered. Late cases of renal vein thrombosis have been associated with recurrence of membranous nephropathy, (Carrasco A, 2008).
\n\t\t\t\n\t\t\t\tClinical presentation and diagnosis:\n\t\t\t
\n\t\t\tThe symptoms is nonspecific as the sudden onset of hematuria, oliguria or anuria, accompanied by local pain and swelling of the graft. There may also increase the diameter of the ipsilateral lower limb deep venous thrombosis associated. The evaluation of renal Doppler ultrasound confirms the increase in renal volume and absence of venous flow. In the arterial can be seen reverse diastolic flow. Although it has been reported that early surgical exploration and thrombectomy allow the preservation of the graft in cases with renal vein thrombosis, but usually the kidney is no longer viable at the time of surgical exploration due to the spread intrarenal venous thrombus and prolonged hypertension. In most cases the nephrectomy is performed (Fathi T, 2007).
\n\t\t\tA complication associated with renal vein thrombosis is the rupture of the graft, which may cause hemorrhage and large hematoma perinephric (confirmed by ultrasonography), together with signs of hypovolemia and circulatory shock. Physical examination usually reveals bulging at the site. Nephrectomy is also standard procedure (figures 9, 10).
\n\t\t\tHowever, in cases of rupture of the graft without thrombosis, should be attempted to suture the parenchyma and preservation of the graft (Gang S, 2009).
\n\t\t\tNephrectomy: Renal vein thrombosis.
Renal vein with thrombus inside and graft’s rupture.
Lymphocele is a lymph collection from the iliac lymphatic vessels of recipient or graft hilum that accumulates between the transplanted kidney and bladder. The average incidence of lymphocele in the literature ranges from 0.6 to 16% (\n\t\t\t\t\tAdani, Baccarani et al. 2007\n\t\t\t\t; Zargar-Shoshtari, Soleimani et al. 2008; Iwan-Zietek, Zietek et al. 2009). The etiology has been attributed to inadequate ligation of the delicate lymph vessels overlying the iliac vessels or present in the hilum. The method of renal uptake also appears to influence the appearance of lymphatic complications. The removal of the kidney by laparoscopy may prolong the lymphatic leak requiring drain for a longer period (Saidi, Wertheim et al. 2008). The small lymphoceles are more frequent but usually asymptomatic (Krol, Kolonko et al. 2007).
\n\t\t\tHowever, larger collections are manifested clinically in a few weeks to months after transplantation, bulging can occur in the surgical wound (Fig. 11) with or without cutaneous extravasation of lymph. In severe cases, there may be edema of lower limb ipsilateral to the graft, frequent urination due to bladder compression and ureteral obstruction leading to hydronephrosis and loss of renal graft function (Kahan and Ponticelli 2000)
\n\t\t\tAbdominal bulging secondary to lymphocele.
The diagnosis is confirmed by ultrasound which may show hydronephrosis, altered vascular flow by Doppler and quantify the lymphocele or the presence of other collections such as hematoma (Fig. 12) or urinoma (Fig. 13)(Krol, Kolonko et al. 2007). In cases of doubt about the etiology, a computerized axial tomography (CT) (Fig. 14) can be performed following puncture of the collection guided by CT or ultrasound (US) with biochemical dosages of the liquid obtained.
\n\t\t\tThe treatment can be divided into expectant, puncture and drainage or surgery. As previously mentioned, small volumes of lymphocele with less than 140ml and asymptomatic, tend to resolve spontaneously without any renal graft damage. Larger collections or lymphoceles with clinical manifestations can be punctured and drained, under strictly aseptic techniques and guided by US or CT. In this case you should aim for total disappearance of the collection. If there is clinically significant recurrence, a sclerotherapy with povidone-iodine 5% ethanol or antibiotics can be performed (Chandrasekaran, Meyyappan et al. 2003; Hamza, Fischer et al. 2006; Zomorrodi and Buhluli 2007).
\n\t\t\tPerinephric hematoma
Urinoma.
Computerized axial tomography showing a lymphocele.
In lymphoceles larger than 500 ml, punctures, drainages and sclerotherapy are usually not effective. In cases refractory or complicated, the laparoscopic lymphocele fenestration (Marsupialization) is the procedure of choice in many centers. The laparoscopic technique reduces the risk of injury to the ureter or infection and demonstrates high rate of success. It is important to create a window sufficiently large to ensure patency of the ureter (Kahan and Ponticelli 2000).
\n\t\t\tWhen the location is not favorable to laparoscopy or in recurrent cases, the approach by open surgery should be performed, especially when the lymphocele is located posterior and lower to the transplanted kidney or behind the bladder (Fuller, Kang et al. 2003; Hamza, Fischer et al. 2006). In both techniques is recommended to perform the peritoneocystostomy with an oval window of at least 2.5 x 5.0 cm in width associated with interposition of short segment of omentum, allowing a good peritoneal absorption of lymphocele and avoiding internal hernias of the bowel segments (Kahan and Ponticelli 2000).
\n\t\t\tRecently was reported the treatment of recurrent and symptomatic lymphocele by inserting a Tenchoff catheter at the site of lymphocele tunneled to the abdomen, allowing the intraperitoneal drainage. This procedure offers as advantages the possibility of being performed in outpatient clinics, without general anesthesia, with good efficacy and safety, although the number of cases reported is still small (\n\t\t\t\t\tAdani, Sponza et al. 2007\n\t\t\t\t) (\n\t\t\t\t\tAdani, Baccarani et al. 2007\n\t\t\t\t).
\n\t\t\tIn conclusion, the treatment of lymphoceles should begin by less invasive techniques. If there is recurrence or failure proceed to marsupialization by laparoscopy or open surgery.
\n\t\tCandidiasis is the common name for diseases produced by the yeast of the genus Candida. This is the most frequently found yeast in human microbiome and is capable of causing disease at different sites of the human anatomy and with diverse severity [1]. Invasive candidiasis refers to severe fungal infections in which the yeast might be found in deep organs or blood [2]. Due to the difficulty of identifying Candida yeasts in tissues, since it requires a biopsy of the tissue compromised, invasive candidiasis in the literature has been primarily found as bloodstream infections, alone or with accompanying tissue compromise.
Candida species are yeasts (i.e., they mainly have a unicellular form). They are small, with a size of 4–6 μm, with a thin wall and an ovoid aspect, named blastospores [3]. They reproduce by budding. Using the microscope, these yeasts can be seen in the form of pseudohyphae, budding cells that do not separate, or truly hyphae (multicellular organisms). Candida organisms belong to the class Ascomycetes, order Saccharomycetales, and family Saccharomycetes [4]. There are around 200 species of Candida; however, a limited number has a pathogenic effect on humans [4]. Table 1 shows the most frequently found species. Due to their previous prevalence and pathogenic significance, they were usually classified as albicans versus non-albicans Candida species. However, due to changes in epidemiology, this overall classification might not be useful any more.
Species | Characteristic |
---|---|
C. albicans | Usually the most frequently found |
C. parapsilosis complex | C. parapsilosis, C. orthopsilosis, C. metapsilosis |
C. tropicalis | Related to cancer |
C. glabrata | Usually resistant to azoles, seen more frequently in developed scenarios and older patients |
C. guilliermondii | Less pathogenicity |
C. lusitaniae | Potentially resistant to amphotericin |
C. krusei | Intrinsically resistant to azoles |
C. dubliniensis | Difficult to differentiate from C. albicans |
C. auris | Responsible for a global outbreak |
Most frequently found Candida species in human disease.
They grow in agar as colonies with a smooth, creamy, white appearance. The formal identification can be made by use of biochemical physiological reactions, which can differentiate an important number of isolates. The metabolic reactions include carbohydrate fermentation, nitrate use, and urease production.
Candida yeasts might be seen with direct stains like KOH with 10–20% concentrations, but also with others like Gram, Giemsa, Wright para amino-salicylic (PAS) acid, and Papanicolaou. In direct stains, Candida might be seen as big aggregates of blastoconidiae, with short and large pseudohyphae. Usual growth media include Sabouraud agar, brain infusion, heart, and yeast extract. While C. albicans and C. dubliniensis grow in usual Sabouraud agar with antibiotics, some species might be inhibited by cycloheximide [4]. Usual growth time is 2–3 days at 28–37°C. Chromogenic agars were developed more than 20 years ago and are capable of identifying the most commonly found species, and speciation is desirable due to pathogenic and susceptibility differences among them. There are several commercial methods using chromogenic agars. The sensitivity for detection of Candida yeast is over 95%, usually with a low number or no false positive results [5]. The finding of a positive culture does not imply an invasive infection, and a special consideration has to be made for isolates from sterile sites.
Candida species differ in their susceptibility to different antifungals available in different countries. Most frequently found isolates of C. albicans and C. parapsilosis are susceptible to all antifungals available. C. tropicalis might have some resistance to fluconazole, while maintaining susceptibility to equinocandins and amphotericin B. C. glabrata tends to have higher minimal inhibitory concentrations (MICs) to azoles, while remaining susceptible to equinocandins and amphotericin B. C. lusitaniae isolates can be found to be resistant to amphotericin B. The recently found that C. auris is frequently found multidrug resistant.
Susceptibility testing can be performed by different methods, including broth microdilution (recommended in the USA and Europe), but there are other different commercial methods available in hospitals. Two slightly different standards for susceptibility testing are currently available. One is suggested by the Clinical Laboratory Standards Institute (CLSI, in USA), while the other is proposed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), sponsored by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Basic differences between both methodologies include time and instrument to read the results. Different clinical breakpoints have been established for the most commonly found species, with the intention of differentiating the risk of clinical failure after treatment. The experience with fluconazole has allowed to develop better prediction models, in comparison with newer antifungals [6]. In summary, an isolate of Candida is exposed to different concentrations of the antifungal and the in vitro growth is observed. If there is no important growth, determined optically or by a spectrophotometer, a minimal inhibitory concentration (MIC) is established. As mentioned, data from clinical trials and observation cohorts with common species such as C. albicans and C. glabrata have allowed to identify clinically relevant breakpoints to differentiate isolates with low MICs (susceptible); intermediate MICs (also called susceptible dose dependent—SDD), in which an increase in the administered antifungal can control the infection; and high MICs, (resistant), for which a lower probability of success is expected. For some other uncommon species, only epidemiological breakpoints are available. These breakpoints are also MICs, but there is no clinical evidence of correlation with the clinical outcome after treatment. However, since MICs are higher than those in usual isolates, a worse outcome might be expected. These breakpoints are expected to identify isolates with natural or acquired mechanisms of antifungal resistance. The epidemiological breakpoints are based on the statistical distribution of MICs of the wild-type isolates (i.e., isolates without any previous resistant pressure). Commercial methods are modifications of the standard methods that use dyes to identify the growth (e.g., Alamar Blue) of the microorganisms. Examples include Sensititre™ and YeastOne™. Other methods are based on agar, in which a gradient of the antifungal is diffused in the solid growth media, which allows to directly read the MIC (e.g., Etest ™) [7].
Candida species are part of the human microbiota and they live in human mucosae and skin. Candida species can be found in the ground, animals, fruits and vegetables, and in the hospital environment. It is not considered a laboratory contaminant. It is considered an endogenous pathogen since around 60–75% of the people might have it in the mucosal epithelium, especially in the gastrointestinal and genital tracts [8]. In the hospital area, they have been found over inanimate surfaces, including percutaneous catheters and tubes. They might even be found in the hands of healthcare workers. Among patients in healthcare centers, the colonization of the mucosae has been related to antibiotic use and hospitalization time [9]. In patients in the intensive care unit (ICU), colonization might be found in different anatomical sites with ample variations [10, 11]. Pharyngeal colonization rate has been found to be between 34 and 65%, gastric colonization between 42 and 67%, rectal colonization between 21 and 40%, and colonization in other sites between 11 and 40% [10, 11]. These data show the possibility of colonization that has this microorganism in patients under stress conditions (in this case, severe disease). In the normal host, the colonization rate might reach over 50% in the mouth, 40% in the vaginal tissue in women, and 73% in any mucosa of the gastrointestinal or genital tracts [8].
Candida species have some characteristics that permit them to adapt to different environments and act as an opportunistic pathogen. These factors include adaptation to pH changes, permitting to survive in blood or some alkaline environments, as well as in the acidic environment of the vaginal tissue; these species have adhesins, mannoproteins with capacity to adhere to different cells and cell products. These adherence proteins allow the isolates to survive in tissues, but also over inanimate surfaces that have been exposed to plasma or inflammatory host proteins like urinary or endotracheal catheters. Candida species have also important enzymes as virulence factors, since some of them have keratinolytic, peptidase, hemolysin, and other effects. One of the most frequently mentioned virulence factors include the possibility of a morphologic transition, which has been extensively studied. It refers to the possibility of morphologic changes of blastoconidia to pseudohyphae to real hyphae. These changes are stimulated by environmental conditions. The filamentous forms are related to active infection in the host, except for C. glabrata. Other factors related to pathogenicity or virulence also include a phenotyping change, the possibility of adopting different phenotypes in the cultures (color or aspect of the colonies), and biofilm formation. A biofilm is a large community of symbiotic microorganisms adhered to a surface. This conformation allows the microorganisms to have a highly defensive capacity, persistence, and a highly antimicrobial resistance.
As mentioned before, Candida might be part of the human flora. The majority of infections are due to the interplay between the risk factors, that pose a risk to the individual, the interaction with other microorganisms present in the skin or mucosa and the total quantity of microorganisms present. This was demonstrated some years ago in an experiment [12]. An individual ingested directly from a C. albicans culture. After some hours, this immunocompetent individual began to have fever. After 12 hours, Candida isolates were found in the bloodstream and, after 16 hours, they were found in the urine. After 24 hours, Candida isolates were cleared from the body and the individual returned to the normal state. This experiment proved the importance of colonization. With posterior evidence, it has been demonstrated that the first step to have an infection is colonization by Candida especially in the gastrointestinal tract, but otherwise in contact with indwelling catheters, the skin, or wounds that may permit the entry of the yeast into the bloodstream. In another critical observation, patients in the ICU were followed with cultures. The colonization index (it is the proportion of positive cultures for the same Candida species taken from different anatomical places) increased over time and was correlated to the probability of developing an invasive candidiasis [9]. These studies suggest that in individuals with Candida colonization, those factors that promote the grow of the yeast, by eliminating the bacteria that can compete for the environment, that alter or facilitate the penetration of the yeast to the bloodstream (lesions in the gastrointestinal mucosa, indwelling catheters) will promote the entry of Candida yeast to the blood, while the net state of compromise of the immune system will affect the probability of fungal clearance and the possibility of seeding on specific organs.
Patients in the ICU have the highest rate of Candida infections in the hospital. In comparison with patients in other wards, patients in the ICU have more frequent abdominal surgery, stay longer in the hospital, and are more severely ill [13]. They also have a worse prognosis in the long term, with increased mortality after one year of the event.
Patients in the ICU have higher rates of Candida infection in comparison with patients in other wards. Critically ill patients often require multiple vascular and other indwelling devices for their management and candidemia has been related to catheter colonization in 20–80% of the cases [14, 15]. One study in Japan identified the presence of a solid tumor, the use of total parenteral nutrition, and the administration of anti-anaerobic agents as the main risk factors for the development of Candida infections [16]. As mentioned, Candida colonization of the catheter might provide a route for entering into the bloodstream without a heavy gastrointestinal colonization. Studies have shown that Candida catheter-related bloodstream infections have a shorter time to grow in comparison with those from other sources [14]. With a breakpoint of 30 hours, the time to grow in patients with Candida bloodstream infection might identify 100% of those catheter-related infection. Probably, patients with catheter-related infection have a higher inoculum, which would explain the faster time to grow and the fact that observational studies have shown a lower mortality when catheter is removed [17, 18]. On the other hand, patients with non-catheter-related candidemia were more seriously ill, had a higher mortality, and the removal of the catheter did not affect the outcome [17].
Another commonly identified risk factor is the use of parenteral nutrition or the length of its use [15, 19]. This group of patients shares several risk factors, but parenteral nutrition has been identified in multivariate analysis [20]. Usually, they have an abdominal procedure (see below) and they require parenteral nutrition for several days. Lack of appropriate measures to handle the nutrition, colonization of the catheter or the ports used to infuse it, and probably the availability of optimal growing conditions are conditions related to its use. But clearly, the use of parenteral nutrition leads to the development of mucosal atrophy and a loss of mucosal epithelial barrier function [21], which might affect the relationship between microorganisms in the gut and the possibility of gaining access to blood vessels. Total parenteral nutrition has also a profound effect in the gastrointestinal microbiome [22].
Several studies have shown the relationship between candidemia and a previous surgical procedure [19, 23], specially an abdominal surgery. There are several explanations to this observation, but gut manipulation, and the effect of resected sections over the gut microbiology, microbiota abundance, and epithelial function might contribute to the possibility of candidemia. Studies have shown that patients with high anastomotic leak, as well as those with recurrent gastrointestinal perforation, or acute necrotizing pancreatitis, have a higher risk of candidemia [15].
Almost all studies of candidemia have shown an extremely high use of antibiotics previous to the identification of bloodstream or tissue infection. The proportion of patients with antibiotic use is over 80% [24]. The number and spectrum of the antibiotics used might affect the risk of candidemia. Antimicrobials also have an effect over gut microbiota, and some studies have shown some impact from antibiotics with anti-anaerobic effect, and those with higher gastrointestinal concentration [25]. They contribute to the observed increased colonization over time observed in patients in the ICU. With more antibiotic effect, there is a net decrease in the number of species in the gastrointestinal tract, an increase in the number of patients colonized, and the proportion of them being heavily colonized [26].
Studies have identified several risk factors that alone, or in combination, might increase the probability of having candidemia. The presence of renal failure, the use of antihistaminic blockers, the severity of illness, and the length of stay in the ICU contribute to colonization and development of candidemia [24, 27]. All these factors contribute to the acquisition of Candida, its colonization, or failure in the gastrointestinal epithelial function, favoring the entry of the yeast to the bloodstream.
The identification of risk factors lead to the use of some scores based in the presence of such factors to identify patients with higher risk of Candida infection. The first and most simple of those scores was introduced in mid-1990s. Pittet et al. in a surgical ICU followed prospectively patients admitted in the ward with cultures of several anatomical sites [9]. They defined the colonization index as previously stated, establishing that with an index of 0.5 or more (50% of the sites with the same species), there was an increase in the risk of candidemia. With a lower colonization index, the risk in the original study was 0%. They defined a second index based on the density of colonization, in which patients overpassing some thresholds in the number of colonies isolated per site, being able to improve the identification of the patients at risk.
A second score to identify risk factors in patients was developed in Spain by León and his collaborators [20]. They identified colonization (with a different definition from that used by Pittet et al.), surgery at ICU admission, and use of total parenteral nutrition as risk factors independently associated with candidemia. They also identified sepsis as independently related, but this is clearly more a clinical syndrome than a risk factor. A third score was developed by a multicenter collaboration group, in which they again identified the same risk factors [28]: antibiotic use, having an intravascular catheter, in conjunction with at least two additional risk factors such as any surgery, immunosuppressive use, pancreatitis, total parenteral nutrition, dialysis, or steroid use.
Common to these scores has been the presence of the aforementioned risk factors. The problem, however, is that such scores identify a huge number of patients at risk with a final intermediate risk of developing candidemia, in a range from 7 to 30% [29, 30]. The great advantage of the diagnostic scores relies in their high negative predictive value. Patients with a negative score have a low probability of candidemia, below a 1% probability.
These disorders share a common factor: immunosuppression. However, different types of immunocompromise entail different risks for the patients. The incidence of candidemia among patients with cancer is higher in comparison with other patients in the hospital. In a multicenter study in Greece, patients with hematological disease had an incidence of candidemia of 1.4 cases per 1000 admissions, while other patients hospitalized had an incidence of 0.83 cases per 1000 admissions [31]. A multicenter European study found an incidence of 1.2% cases of candidemia among patients with bone marrow transplantation (BMT) and leukemia [32]. An Italian multicenter study from a surveillance network showed a diminishing trend for candidemia among patients with cancer, especially among those with acute myeloid leukemia [33]. Whether this trend can be inferred to other European countries or not is not known, and the most likely explanation for this decrease in the number of cases could be related to the use of prophylaxis among those patients with acute leukemia with posaconazole. In general, non-albicans Candida species are more frequently found among these groups of patients [31].
Neutropenia, a count of leukocytes in peripheral blood below 500 cells per μl, is the common risk factor among patients with hematological disorders (i.e., leukemia, lymphoma, multiple myeloma among others) as well as those with bone marrow transplantation (BMT). Neutropenia might be a consequence of the activity of the hematological disease, an effect of chemotherapeutic strategies or side effect of multiple medications including antimicrobials. It also is a marker of the intensity of chemotherapy. Patients with chemotherapy-induced neutropenia accumulate various risk factors: they usually receive wide spectrum antibiotics for several days, they have serious gastrointestinal epithelial tissue dysfunction, usually with diarrhea and signs of mucosal damage, and the use of vascular catheters for the infusion of chemotherapeutic drugs and antibiotics [34]. Several studies have shown that isolates of C. tropicalis are more frequently found among patients with cancer [35]. A study that looked for risk factors identified underlying leukemia as one of the major risk factors, together with chronic lung disease [36].
In patients with prolonged neutropenia, a condition called hepatosplenic candidiasis might be seen. In it, seeding of yeasts occurs during the neutropenic phase which might be not clinically evident until neutropenia recovery. In these patients, fever persists and lesions can be seen in the liver, usually known as bull-eye lesions [37] (Figure 1).
Tomographic image of liver and spleen showing abscesses (bull’s eye, arrows) and hypodense lesions in a patient with chronic disseminated candidiasis. Reproduced with permission from Cortés et al. [37].
In patients with cancer and candidemia, several factors were identified in comparison with those with cancer and bacterial infections [38]. Total parenteral nutrition over 5 days, urinary catheter for more than 2 days, distant metastasis of cancer, and gastrointestinal cancer were independent risk factors. Patients with solid tumors might accumulate factors as patients in critical care, since they have abdominal surgery (gastrointestinal neoplasm), require vascular catheters for extended periods of time (for chemotherapy or antibiotics), total parenteral nutrition and received antibiotics frequently [39]. A study to identify factors predicting catheter-related infections with Candida identified solid tumors and the use of anti-anaerobic antibiotics as risk factors [16].
Among patients with leukemia and BMT, the risk factors for occurrence of candidemia included bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft versus host disease [32]. These data were derived from a huge multicenter registry of patients with cancer and transplantation, which allowed to identify more precisely the risk factors.
Newborns have no gastrointestinal flora at birth and have to be colonized by enterobacteria and other microorganisms, which is made via maternal breast feeding. Any alteration in the normal process can lead to colonization by pathogenic microorganisms, including yeasts [40]. Neonates in the intensive care unit usually have limited breastfeeding, indwelling vascular catheters, total parenteral nutrition, and antibiotics [41]. Such combination of risk factors put. this group of patients at a higer risk of infection, reaching over 10% of patients in units with extreme prematures and low weight at birth (the group that requires more invasive interventions) [42]. Some studies have illustrated this relationship with proportion of candidemia between 3 and 10% among those with a weight of less than 1000 g while showing an incidence of less than 1% for those weighting over 2500 g [43]. In this scenario, disseminated candidemia can be found and near 10% of those with invasive disease can compromise the central nervous system. Another important risk factor includes the time that the patient has been in the unit [44]; clearly, patients with low weight, lower gestational age, and more comorbidity tend to spend more time in the neonatal ICU and to accumulate other risk factors (surgery, indwelling catheter, antibiotics, etc.) [45]. There are some high-risk units, in which the incidence of candidemia traditionally has been high, usually over 10% of the admitted cases. In this scenario, prophylaxis has been suggested for the prevention of infection [46].
Candida yeast can survive in inanimate surfaces and in the hands of healthcare personnel, which confers the risk of outbreak and cross dissemination among high-risk units such as neonatal, intensive care, and surgical intensive care units [44, 47]. An interesting study in Iceland over a long period of time allowed to confirm the presence of clonal isolates of different Candida species among patients in the ICU and other wards [48]. The proportion of patients involved at one time with an outbreak of all patients with Candida isolates might be as high as 38%. Other study in Spain showed that clusters (of patients with candidemia) were possible with C. albicans and C. parapsilosis, and reached in a period as high as 40% of the isolates [49]. Besides, the use of chlorhexidine has been shown to diminish the number of candidemia events in patients in the ICU, showing the importance of colonization and cross infection among high-risk patients and establishing this recommendation in the guidelines for the prevention of candidemia [50].
As shown, colonization is the preliminary step to infection. Besides, a number of interventions are common to immunosuppressed and critically ill patients including indwelling catheters (urinary and vascular), severity of illness, total parenteral nutrition, etc. These conditions predispose the patients to cross contamination. An outbreak among newborns was demonstrated to be due to poor practices of catheter ports disinfection [51].
A study in China in a cancer institute showed that 21 out of 36 episodes of candidemia were caused by two endemic genotypes [52]. In this study, gastrointestinal cancer and insertion of a nasogastric tube were related to infection. As mentioned before, cancer patients with solid and hematological tumors share several of the risk factors of colonization and infection.
Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated an important effort to know the epidemiology and burden of fungal infections around the world and allowed a better understanding of their epidemiology in different countries [53]. The real incidence of candidemia is difficult to calculate due to differences in the approach. While studies based on hospitals might overestimate the importance of some groups of high-risk patients, they are difficult to compare. Data from population studies might reflect better the real situation, but this kind of information is scarce. Studies have shown ample differences in the incidence in some regions and at specific times [54].
Traditionally, C. albicans had been the most frequently isolated species. However, a trend toward non-albicans species has been observed around the world in the last 15 years. In United States, C. glabrata has been identified as second in frequency, while C. parapsilosis or C. tropicalis dispute this place in other regions. Table 2 shows the proportion of isolates in some studies around the world in the last 10 years [55, 56, 57, 58, 59].
Area and publication year | C. albicans (%) | C. glabrata (%) | C. tropicalis | C. parapsilosis | References |
---|---|---|---|---|---|
USA 2012 | 38 | 29 | 17 | 10 | [49] |
Latin America 2013 | 37.6 | 6.3 | 17.6 | 26.5 | [48] |
Spain 2014 | 45.4 | 13.4 | 7.7 | 24.9 | [50] |
Asia-Pacific region 2016 | 20–55 | 5–22 | 2–20 | 8–27 | [51] |
France 2014 | 56 | 18.6 | 9.3 | 11.5 | [52] |
Proportion of Candida species in selected studies of candidemia around the world.
Two studies deserve a detailed description. The first one is a multicenter study from the Southeast Asia region, including 25 hospitals from 6 countries: China, Hong Kong, India, Singapore, Taiwan, and Thailand [60]. They found differences between the countries that include the frequency of C. tropicalis isolation, being more commonly found in hematology-oncology wards and in tropical areas. This study confirmed the observed trend for a lower frequency of C. albicans isolates. The other study is the Latin-American surveillance study [55]. It involved patients from 20 centers in 7 seven countries: Argentina, Brazil, Colombia, Chile, Honduras, Mexico, and Venezuela. Important differences were seen among institutions, reflecting difference in healthcare systems, access, population types, and risk factors. However, in these two studies, the incidence of candidemia is higher than in developed countries in Europe and North America. In Latin America, C. parapsilosis frequency is over 30% of the isolates while this place is occupied by C. tropicalis in the Asian countries.
There are data from some population surveillance surveys in Europe and United States. In general, the incidence might be lower than in some other areas of the world. Table 3 shows the incidence from data from North America and European countries [61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77]. In Europe, the highest incidence has been observed in Hungary, while in North America the highest incidence has been seen in some cities in United States.
Country/region | Publication Year | Incidence (per 100.000 inhabitants) | References |
---|---|---|---|
Belgium | 2015 | 5 | [54] |
Denmark | 2008 | 10.4 | [55] |
Finland | 2010 | 2.8 | [56] |
Germany | 2015 | 4.6 | [57] |
Hungary | 2015 | 11 | [58] |
Ireland | 2015 | 7.3 | [59] |
Norway | 2018 | 3.8 | [60] |
Portugal | 2017 | 2.57 | [61] |
Romania | 2018 | 6.8 | [62] |
Russia | 2015 | 8.29 | [63] |
Serbia | 2018 | 10 | [64] |
Spain | 2015 | 8.1 | [65] |
Sweden | 2013 | 4.2 | [66] |
Ukraine | 2015 | 5.8 | [67] |
Canada | 2017 | 2.91 | [68] |
México | 2015 | 8.6 | [69] |
USA | 2015 | 9.5–14.4 | [70] |
Estimated incidence of invasive candidiasis or candidemia in countries of the European or North American regions.
This region has profound differences in healthcare systems, access to care, and medical technology development. With a transition toward a higher income, a growing number of institutions with capacity to attend cancer patients, and more complex medical needs, the number of candidemia cases seems to be higher than in developed countries.
Ample information exists about the problem in Brazil, where a number of studies have been carried out in high-complexity hospitals in the main cities of the country [78, 79]. These studies show a higher frequency of invasive candidiasis in comparison with developed countries, an increased isolation of C. glabrata for the last period and an important exposition to fluconazole (which might have increased the selection for non-albicans species) [79]. Country-wise estimates for incidence are shown in Table 4 [80, 81, 82, 83, 84, 85, 86, 87, 88, 89].
Country/region | Publication year | Incidence (per 100,000 inhabitants) | References |
---|---|---|---|
Argentina | 2018 | 6.25 | [71] |
Brazil | 2016 | 14.9 | [72] |
Chile | 2017 | 5.8 | [73] |
Colombia | 2018 | 14.7 | [74] |
Ecuador | 2017 | 7.2 | [75] |
Guatemala | 2017 | 6.4 | [76] |
Jamaica | 2015 | 5.8 | [77] |
Perú | 2017 | 5.8 | [78] |
Trinidad and Tobago | 2015 | 5.8 | [79] |
Uruguay | 2018 | 36.5 | [80] |
Estimated incidence of invasive candidiasis or candidemia in countries of Central and South America and the Caribbean.
A multicenter in Asia gathered information from various countries, including nine hospitals from China [60]. The incidence rate among patients hospitalized was 0.38 per 1000 admissions, which is lower than that observed in the Latin-American region with 1.08 cases per 1000 admissions [55]. The estimated incidence of candidemia in countries in Asia is shown in Table 5 [90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100]. In Asia, the highest incidence has been observed in Pakistan, followed by Qatar and Israel. In China, geographic variations in the causative species and susceptibilities were noted, with increasing isolates resistant to fluconazole [101]. The numbers for the African countries are lacking and for some countries like Algeria, Burkina Faso, Cameroon, Egypt, Malawi, Mozambique, and Tanzania, the estimated incidence is 5.8 cases per 100,000 inhabitants, a standard calculation based on previously reported incidence in other countries [102, 103, 104, 105, 106, 107, 108].
Country/region | Publication year | Incidence (per 100,000 inhabitants) | References |
---|---|---|---|
Bangladesh | 2017 | 5 | [83] |
Israel | 2015 | 11 | [84] |
Jordan | 2018 | 5.75 | [85] |
Kazakhstan | 2018 | 4.3 | [86] |
Korea | 2017 | 4.57 | [87] |
Malaysia | 2018 | 5.8 | [88] |
Pakistan | 2017 | 21 | [89] |
Philippines | 2017 | 2.25 | [90] |
Qatar | 2015 | 15.4 | [91] |
Thailand | 2015 | 13.3 | [92] |
Uzbekistan | 2017 | 5.93 | [93] |
Estimated incidence of invasive candidiasis or candidemia in countries of Africa and Asia.
Azole-resistant Candida isolates have had an increased frequency over the years. Susceptibility changes with the species, and fluconazole use has been related to an increase in the frequency of C. glabrata and C. krusei, and a low increase in the number of resistant C. albicans or C. tropicalis. A large multicenter study in French ICUs identified the age and the exposure to antifungals as independent risk factors for resistance [109]. Patients with isolates resistant to fluconazole tended to be older than 15 years and to have been exposed to this drug, while those with equinocandin-resistant isolates were younger and found to have been exposed to equinocandin. In general, risk factors for resistance remain the same as in resistant bacteria: immunosuppression, previous use of antifungals [110, 111]. Other identified risk factors include chronic renal failure and anti-tuberculous treatment. This last one might be due to a medication interaction.
Among patients with cancer, not only are non-albicans Candida species more frequently found, but also resistance to azoles has increased. In a study in Greece, resistance to fluconazole among patients with cancer reached 27% [31]. Since azoles have been widely used in the prophylaxis against fungal infections among cancer patients [112, 113], this seems to be a natural consequence of their use. Among patients with cancer, isolates of C. tropicalis, C. glabrata, and C. krusei have increased resistant proportions [35].
Up to 2009, there was no report on C. auris. In that year, a clinical case from Japan was published, and 2 years later three cases of candidemia were identified [114, 115]. During the following years, isolates of C. auris were responsible of outbreaks around the world, affecting hospitals in India, Pakistan, South Africa, England, and Venezuela [116, 117, 118, 119]. It was detected in the USA in 2013 with growing frequency [120]. A worldwide alarm was raised in 2016 because of two problems related to this species. The first one was the difficulty in proper identification [121]. C. auris is most commonly identified as C. haemulonii and Rhodotorula glutinis by the commercial systems and sometimes as C. famata, C. guilliermondii, and C. parapsilosis [121]. The other problem is the higher frequency of resistance to multiple antifungals, including azoles and amphotericin [122]. Currently, C. auris has been isolated in several areas in the USA, continental Europe, and the Caribbean coast of South America, including the islands [123, 124, 125], and continue to extend to other areas, where reports are being published. A search for virulence factors in the isolates of C. auris has shown some different properties, specially the capacity for biofilm formation [126]. Molecular observations have diverse geographic dissemination caused by unique clades in each geographic region [127].
Patients with candidemia and cancer are considered to have higher mortality, but this issue has not been clearly assessed. Older studies showed an attributable mortality around 40%. Although mortality among patients with candidemia or invasive candidiasis is reported usually around 40–50%, they occur in patients with important comorbidity. A recent multicenter analysis showed a crude mortality for patients with candidemia of 53%, while those without candidemia had a mortality of 26% [128]. After adjusting in a propensity score analysis, the crude mortality was 51% for the candidemic patients and 37% for the others and the difference was not statistically significant. The study shows that an increase in mortality might exist for those patients with candidemia, but it is clear that patients with candidemia also have severe comorbidity and some of them can die with candidemia instead of because of it.
Risk factors for mortality among patients with candidemia include ascites, presence of septic shock, ICU admission, concomitant bacterial infection and catheter-related infections [129]. Studies with diverse population have shown that elderly patients have higher mortality [130]. In these patients, a combination of comorbidity, poor clinical situation, and more pathogenic species might contribute to their mortality [131]. A pooled analysis from patients included in randomized clinical trials comparing micafungin and amphotericin B showed differences among geographic regions, severity of disease (measured with Apache score for patients critically ill), and catheter removal [132]. In those with abdominal candidiasis, the lack of control of the source of infection has been related to increased risk of death [133]. Among patients with cancer, risk factor for mortality includes infection by a C. tropicalis isolate, a high Charlson index score, neutropenia, and septic shock [35, 134]. One multicenter study identified tachypnea as a risk factor for mortality [135], while others identified respiratory failure and use of non-antifungal medications [39]. Besides, antifungal prophylaxis and remission of the underlying cancer had a protective effect over mortality [135].
The impact of the antifungal treatment in the mortality of patients with candidemia is not entirely clear. There are several constrains to identify the benefits of the antifungal treatment: An important proportion of patients did not receive antifungal treatment despite the identification of a bloodstream infection; of those that receive the treatment, some of them can receive it as empirical treatment, based on the risk factors, clinical condition, while others have an antifungal started upon detection of candidemia. Besides, some of them are infected with a resistant isolate and some do poorly, and an additional antifungal must be started. Although meta-analysis with patient-level data has showed the benefit of equinocandin use (in contrast to azole treatment) [136], neither the cohort data [137], nor the randomized trials have confirmed this finding [138]. There is an additional complication in understanding this relationship; the laboratory breakpoints for identification of susceptible versus resistant isolates have changed over the time, especially for azoles [130]. Among those patients with septic shock, the delay in the administration of the antifungal treatment has been associated with increased mortality.
Candidemia is the most frequently found form of invasive candidiasis. The Candida species might be found as part of the flora and patients with previous colonization are at risk of developing an infection. They share some common factors like antibiotic exposure, use of indwelling catheters, parenteral nutrition, and surgery. These factors affect the normal physiology of the gastrointestinal tract or provide access to the bloodstream to yeast in patients with some comorbidities, in critical care or with immunosuppressive states.
There is no conflict of interest to declare.
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