Complications following renal transplantation vary over time and can be arbitrarily categorized into those occurring early (the first 1–6 months) or late (after 6 months). We concentrate more on the early complications, describe a basic approach to evaluating renal allograft dysfunction in the immediate and early postoperative period, and discuss the urologic and infectious complications commonly encountered in the first 1–6 months following renal transplantation.
Renal Allograft Complications
Delayed Graft Function and Primary Nonfunction
The term delayed graft function (DGF) has been used to describe marginally functioning grafts that recover function only after several days to weeks. In contrast, the term primary nonfunction is best applied to kidneys that never function where allograft nephrectomy is usually indicated.
The incidence of DGF may range from 10% to 50% in some centers and can often be anticipated based on both recipient and donor factors (Table 53–9). Unless these patients have adequate residual urine output from the native kidneys, most will require temporary dialysis support for volume, hyperkalemia, and/or uremia. The differential diagnoses of DGF are shown in Table 53–10. A systematic approach to the evaluation of DGF may be categorized as prerenal (or preglomerular type), intrinsic, and postrenal. Although uncommon in the early postoperative period, vascular causes of DGF must be excluded.
Table 53–9. Risk Factors for Delayed Graft Function Due to Acute Tubular Necrosis in Cadaveric Renal Transplantation ||Download (.pdf)
Table 53–9. Risk Factors for Delayed Graft Function Due to Acute Tubular Necrosis in Cadaveric Renal Transplantation
Age (<10 or >50 years)
African-American (compared to whites)
Donor macrovascular or microvascular disease Cause of death (cerebrovascular versus traumatic)
Peripheral vascular disease
Presensitization (PRA >50)
Preoperative donor characteristics
Perioperative and postoperative factors
Brain death stress
Prolonged use of vasopressors
Recipient volume contraction
Early high-dose calcineurin inhibitors ± early use of OKT3
Organ procurement surgery
Hypotension prior to cross-clamping of aorta
Traction on renal vasculatures
Cold storage flushing solutions
Prolonged warm ischemia time (± contraindication to donation)
Prolonged cold ischemia time
Cold storage versus machine perfusion
Intraoperative hemodynamic instability
Prolonged rewarm time (anastomotic time)
Table 53–10. Differential Diagnoses of Delayed Graft Function. ||Download (.pdf)
Table 53–10. Differential Diagnoses of Delayed Graft Function.
Prerenal (or preglomerular type)
Nephrotoxic drugs (see text)
Arterial or venous thrombosis
Renal artery stenosis
Acute tubular necrosis
Accelerated acute or acute rejection
Recurrence of primary glomerular disease (particularly FSGS)
Perinephric fluid collection (lymphocele, urine leak, hematoma)
Intrinsic (blood clots, poor reimplantation, ureteral slough)
Extrinsic (ureteral kinking)
Benign prostatic hypertrophy
Prerenal Causes of Delayed Graft Function
Intravascular volume depletion and nephrotoxic drugs are the more common causes of prerenal dysfunction. Severe intravascular volume depletion is usually suggested by a careful review of the patient's preoperative history and intraoperative report. Knowing the dialysis dry weight and preoperative weight of patients may be invaluable in the assessment of their volume status in the immediate postoperative period. Both calcineurin inhibitors (CNI)—cyclosporine and to a lesser extent tacrolimus—have been shown to cause a dose-related reversible afferent arteriolar vasoconstriction and a “preglomerular type” allograft dysfunction that manifest clinically as delayed recovery of allograft function. Intraoperative direct injection of the calcium channel blocker verapamil into the renal artery may reduce capillary spasm and improve renal blood flow. Most centers have advocated the use of nondihydropyridine calcium channel blockers (ie, diltiazem) to counteract the vasoconstrictive effect of and to allow a reduction in the dose of the calcineurin inhibitors. Their use may permit the cyclosporine dose to be reduced by up to 40%. Other commonly used drugs that may potentially precipitate acute “preglomerular type” allograft dysfunction include angiotensin-converting enzyme inhibitors (ACEI), amphotericin B, nonsteroidal anti-inflammatory drugs (NSAIDs), and contrast dye.
Intrinsic Renal Causes of Delayed Graft Function
Intrinsic renal causes of DGF typically include acute tubular necrosis, acute rejection, thrombotic microangiopathy, and recurrence of glomerular diseases affecting the native kidneys.
Posttransplant acute tubular necrosis (ATN) is the most common cause of DGF. The two terms are often used interchangeably although not all cases of DGF are caused by ATN. The incidence of ATN varies widely among centers and has been reported to occur in 20–25% of patients (range 6–50%). The difference in the incidence reported may, in part, be due to the more liberal use of organs from marginal donors by some centers but not by others and/or the difference in the criteria used to define DGF. Unless an allograft biopsy is performed, posttransplant ATN should be a diagnosis of exclusion. In the absence of superimposed hyperacute or acute rejection, ATN typically resolves over several days and, on occasion, up to several weeks (4–6 weeks), particularly in recipients of older donor kidneys. Recovery from ATN is usually heralded by a steady increase in urine output associated with a decrease in the interdialytic rise in serum creatinine and eventually in dialysis independence. Prolonged DGF should prompt a diagnostic allograft biopsy to exclude covert acute rejection or other intrinsic causes of allograft dysfunction. The administration of sirolimus in de novo renal transplant recipients may prolong DGF duration without adversely affecting 1-year graft survival.
While hyperacute or accelerated acute rejection due to presensitization may occur immediately following transplantation or after a delay of several days, classic cell-mediated acute rejection is typically seen after the first posttransplant week. Accumulating evidence suggests that there is an interactive effect between ATN and acute rejection. Ischemia reperfusion injury causes upregulation of multiple cytokines and growth factors within the allograft including interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor (TNF), interferon-α (IFN-α), and transforming growth factor (TGF)-β. The proinflammatory cytokine response may in turn trigger acute allograft rejection through upregulation of various costimulatory and adhesion molecules as well as through increased expression of MHC class I and class II antigens. It is therefore prudent to perform a diagnostic allograft biopsy with prolonged ATN.
Thrombotic microangiopathy (TMA) is a well-recognized complication following renal allograft transplantation. It may develop as early as 4 days postoperatively and as late as 6 years posttransplantation. In most cases, calcineurin inhibitors (cyclosporine or tacrolimus) are believed to play a role in the development of this disorder.
Posttransplant TMA may be evident clinically by the typical laboratory findings of intravascular coagulation (such as thrombocytopenia, elevated lactate dehydrogenase levels, and peripheral schistocytes) or it may be covert with inconsistent laboratory findings. In renal allograft recipients, renal dysfunction is the most common manifestation. Thrombocytopenia and microangiopathic hemolysis are often mild or absent. Indeed, the diagnosis of posttransplant TMA is often made on graft biopsies performed to determine the cause of DGF or to rule out acute rejection. Although there have been no controlled trials comparing the different treatment modalities of this condition, dose reduction or discontinuation of the offending agent appears to be pivotal to management. Adjunctive plasmapheresis with fresh frozen plasma (FFP) replacement may offer survival advantages. In transplant recipients with cyclosporine-associated TMA, successful use of tacrolimus immunosuppression has been reported. However, recurrence of TMA in renal transplant recipients treated sequentially with cyclosporine and tacrolimus has been described and clinicians must remain vigilant for signs and symptoms of recurrence of TMA in patients who are switched from cyclosporine to tacrolimus or vice versa. There have been anecdotal reports of the successful use of sirolimus and/or mycophenolate mofetil (MMF) in transplant recipients with calcineurin inhibitor-associated TMA. However, recently, sirolimus has also been reported to cause TMA in renal allograft recipients. Although infrequent, the use of the monoclonal antibody muromonab-CD3 OKT3 has also been associated with the development of posttransplant TMA.
Other potential causative factors of posttransplant-associated TMA include the presence of lupus anticoagulant and/or anticardiolipin antibody, cytomegalovirus infection, and, less frequently, systemic viral infection with parvovirus B19 or influenza A virus. An increased incidence of TMA has also been described in a subset of renal allograft recipients with concurrent hepatitis C virus infection and anticardiolipin antibody positivity.
Recurrence of Glomerular Disease of the Native Kidneys
The incidence of recurrent renal disease after renal transplantation and the risk of graft loss from disease recurrence is shown in Table 53–11.
Table 53–11. Rates of Recurrent Renal Disease after Transplantation and Risk of Graft Loss from Disease Recurrence.1 ||Download (.pdf)
Table 53–11. Rates of Recurrent Renal Disease after Transplantation and Risk of Graft Loss from Disease Recurrence.1
Graft loss from disease recurrence1
Postrenal Causes of Delayed Graft Function
Postrenal DGF is generally due to obstruction and may occur anywhere from the intrarenal collecting system to the level of the bladder-catheter drainage system. The latter is generally due to blood clots and can often be managed by flushing the catheter with saline solution. Nursing care orders should routinely include irrigation of the Foley catheter as needed for clots or no urine flow. In patients with persistent gross hematuria, continuous bladder irrigation may be helpful. However, potential serious complications such as bleeding from vascular anastomoses or graft thrombosis should be excluded. Obstructive uropathy due to perinephric fluid collections or extrinsic compression and ureteral obstruction are discussed further under surgical and urologic complications.
Vascular Complications and Renal Artery Stenosis
Arterial or venous thrombosis generally occurs within the first 2–3 postoperative days but may occur as late as 2 months posttransplant. In most series reported, the incidence of arterial/venous thrombosis ranges from 0.5% to as high as 8% with arterial thrombosis accounting for one-third and us thrombosis for two-thirds of cases. Thrombosis occurring early after transplantation is most often due to surgical complications while late-onset thrombosis is generally due to acute rejection. In patients with initially good allograft function, thrombosis is generally heralded by the acute onset of oliguria or anuria associated with a deterioration of allograft function. Clinically, the patient may present with graft swelling or tenderness and/or gross hematuria. In patients with good residual urine output from the native kidneys but with DGF and an absence of overt signs and symptoms, the diagnosis rests on clinical suspicion and prompt imaging studies. Confirmed arterial or venous thrombosis typically necessitates allograft nephrectomy. Suggested predisposing factors for vascular thrombosis include arteriosclerotic involvement of the donor or recipient vessels, intimal injury of the graft vessels, kidneys with multiple arteries, a younger recipient and/or younger donor age, a history of recurrent thrombosis, the presence of antiphospholipid antibodies (anticardiolipin antibody and/or lupus anticoagulant antibody), and thrombocytosis.
There has been no consensus on the optimal management of recipients with an abnormal hypercoagulability profile such as an abnormal activated protein C resistance ratio associated with factor V Leiden mutation (and to a lesser extent with factor II mutation, prothrombin II 20210 A), antiphospholipid antibody positivity, protein C or protein S deficiency, or antithrombin III deficiency. However, unless contraindicated, perioperative and/or postoperative prophylactic anticoagulation should be considered, particularly in patients with a prior history of recurrent thrombotic events. At our institution, patients with identifiable risk factors are observed intraoperatively for adequacy of hemostasis. If satisfactory, these patients are given a small bolus dose of intravenous heparin (usually 1000 U). Postoperatively, a heparin infusion is continued at 100–300 U/hour. Complete blood counts are checked every 6 hours for the first 24 hours and then daily thereafter. If no bleeding complications are observed, oral warfarin is begun after 48 hours and heparin is continued until a therapeutic INR level is achieved (INR 2.0–2.5). The duration of anticoagulation has not been well defined but lifelong anticoagulation should be considered in high-risk candidates. Transplant of pediatric en bloc kidneys into adult recipients with a history of thrombosis should probably be avoided.
Transplant Renal Artery Stenosis
Although transplant renal artery stenosis may occur as early as the first week, it is usually a late complication. Clinically, patients may present with new onset or accelerated hypertension, acute deterioration of graft function, severe hypotension associated with the use of ACEI, recurrent pulmonary edema or refractory edema in the absence of heavy proteinuria, and/or erythrocytosis. The latter, when associated with hypertension and impaired graft function, should raise the suspicion of renal artery stenosis (RAS) (ie, a triad of erythrocytosis, hypertension, and elevated serum creatinine). The presence of a bruit over the allograft is neither sensitive nor specific for the diagnosis of graft renovascular disease. However, a change in the intensity of the bruit or the detection of new bruits warrants an evaluation. Although noninvasive, a radionuclide scan with and without captopril is neither sufficiently sensitive nor specific for detecting transplant RAS (a sensitivity and specificity of 75% and 67%, respectively). Color Doppler ultrasound is highly sensitive and serves well as an initial noninvasive assessment of the transplant vessels. It should be noted, however, that color Doppler ultrasound is limited by its relatively low specificity. CO2 angiography avoids nephrotoxic contrast agents but its use is not without limitations. Overestimation of the degree of stenosis, bowel gas artifact, and/or patient intolerance have been reported with the use of a CO2 angiogram. Although gadolinium-enhanced MR angiography has previously been suggested to be an alternative non-nephrotoxic method in identifying transplant renal artery stenosis, its use should be avoided in those with allograft dysfuction due to the well-described association between gadolinium and the development of nephrogenic fibrosing dermopathy (NFD) and systemic fibrosis (NSF). Although invasive, renal angiography remains the gold standard for establishing the diagnosis of RAS.
Allograft rejection can be classified as hyperacute, accelerated acute, acute, and chronic.
Hyperacute rejection can occur immediately following vascular anastomosis, which can be recognized intraoperatively by the surgeon, or it may occur within minutes to hours after graft revascularization. Grossly, the kidney allograft may appear flaccid or cyanotic and hard, and graft rupture may occur within minutes after revascularization. Hyperacute rejection is mediated by preformed, cytotoxic immunoglobulin G (IgG) anti-HLA class I antibodies that are produced in response to previous exposure to alloantigens through multiple pregnancies, blood transfusions, and/or prior transplants. These antibodies bind to the graft vascular endothelium and activate complement leading to severe vascular injury including thrombosis and obliteration of the graft vasculature. Hyperacute rejection almost uniformly leads to graft loss, and prevention with meticulous cross-match is the mainstay of management. Hyperacute rejection can also occur as a result of ABO blood group incompatibility due to preformed anti-ABO blood group antibodies. With the current pretransplant cytotoxic cross-match as well as ABO-matching policy, hyperacute rejection has become almost nonexistent.
Recently “pretransplant preconditioning” with plasmapheresis and cytomegalovirus hyperimmune globulin (CMVIg) with or without rituxumab (a humanized CD20 monoclonal antibody) has allowed renal transplantation to be carried out across a positive cross-match and/or ABO blood group incompatibility without the development of hyperacute rejection. These, however, are currently performed only at experienced transplant centers and a discussion is beyond the scope of this chapter.
Accelerated Acute Rejection (Within 24 Hours to 7 Days)
Accelerated acute rejection occurs after the first 24 hours to 7 days after transplantation and may be mediated by both humoral and cellular mechanisms. Accelerated acute rejection probably represents a delayed amnestic response to prior sensitization. It may be seen after donor-specific transfusions in recipients of living-related donor transplant due to a primed T cell response. Treatment of accelerated acute rejection generally requires aggressive treatment with antibody therapy (OKT3 or antithymocyte antibody), intravenous immunoglobulin (IVIG) with or without adjunctive plasmapheresis. Despite aggressive treatment, accelerated acute rejection commonly results in early graft loss. The T cell flow cytometry cross-match (FCXM) may be useful in the pretransplant evaluation of sensitized or reallograft transplant candidates whose antibody levels may have declined but who can mount a rapid amnestic response upon rechallenge. Transplant across a positive T cell FXCM is associated with a higher rate of early acute rejection episodes. Hyperacute rejection, however, has not been reported as long as the pretransplant cytotoxic cross-match is negative. More recently, various desensitization protocols have been developed to allow successful transplantation in sensitized recipients.
Historically, approximately 30–50% of renal allograft recipients have an episode of acute rejection within the first 6 months after transplantation. With the introduction of mycophenolate mofetil (MMF) and anti-IL-2 receptor antibody (anti-IL-2R) daclizumab and basiliximab into clinical practice, acute rejection rates of 15–30% or less have now been routinely achieved by most transplant programs. In the era of cyclosporine and other potent immunosuppressive agents in general, the classic constitutional symptoms of acute rejection including fevers, chills, myalgias, arthralgias, graft swelling, and/or tenderness are often absent. Patients are usually nonoliguric and a rise in serum creatinine may be the only sign of acute rejection. Elevated blood pressure or worsening hypertension may be variably present. Noninvasive imaging studies such as renal Doppler ultrasound or renal radioisotope flow scan is neither sufficiently sensitive nor specific in the diagnosis of acute rejection. Although invasive, allograft biopsy remains the most accurate means of differentiating acute rejection from other causes of acute deterioration of allograft function.
Treatment of Acute Rejection
Because the treatment of acute rejection is a specialized area overseen by the kidney transplant team, the reader is referred to specialty reviews and textbooks for this information.
Surgical and Urologic Complications
Perinephric Fluid Collections
Symptomatic perinephric fluid collections in the early postoperative period can be due to lymphoceles, hematoma, urinoma, or abscesses. Lymphoceles are collections of lymph caused by leakage from severed lymphatics. They typically develop within weeks after transplantation. Most lymphoceles are small and asymptomatic. Generally, the larger the lymphocele, the more likely it is to produce symptoms and require treatment, although very small but strategically placed lymphoceles can result in ureteral obstruction. Lymphoceles may also compress the iliac vein leading to ipsilateral leg swelling or deep vein thrombosis or occasionally produce urinary incontinence due to bladder compression.
Lymphoceles are usually detected by ultrasound either as an incidental finding or during an evaluation of allograft dysfunction. They appear as a roundish, sonolucent, septated mass. Hydronephrosis may be present with a lymphocele adjacent to or compressing the ureter. Generally, the clinical presentation and ultrasound appearance can distinguish a lymphocele from other types of perinephric fluid collections, such as a hematoma or urine leak. Needle aspiration reveals a clear fluid with a creatinine concentration similar to that of serum in the case of a lymphocele, while that of a urine leak would have a much higher concentration.
No therapy is necessary for the common, small, asymptomatic lymphocele. Percutaneous aspiration should be performed if a ureteral leak, obstruction, or infection is suspected. The most common indication for treatment is ureteral obstruction. If the cause of the obstruction is simple compression resulting from the mass effect of the lymphocele, percutaneous drainage alone usually suffices. The ureter is often narrowed and may need to be reimplanted because of its involvement in the inflammatory reaction in the wall of the lymphocele. Repeated percutaneous aspirations are not advised because they seldom lead to dissolution of the lymphocele and often result in infection. Infected or obstructing lymphoceles can be drained externally. Sclerosing agents such as povidone-iodine, tetracycline, or fibrin-glue can be instilled into the cavity with variable results. Lymphoceles can also be marsupialized into the peritoneal cavity, where the fluid is reabsorbed.
An obstructed hematoma is best managed by surgical evacuation. Urinoma or evidence of a urine leak should be treated without delay. A small leak can be managed expectantly with insertion of a Foley catheter to reduce intravesical pressure. This maneuver may occasionally reduce or stop the leak altogether. Persistent allograft dysfunction, particularly in a symptomatic patient, often necessitates early surgical exploration and repair. Infected perinephric fluid collections should be treated by external drainage or open surgery in conjunction with systemic antibiotics.
Ureteral obstruction occurs in 2–10% of renal transplants and is usually manifested by painless impairment of graft function due to the lack of innervation of the engrafted kidney. Hydronephrosis may be minimal or absent in early obstruction, whereas low-grade dilation of the collecting system secondary to edema at the ureterovesical anastomosis may be seen early posttransplantation and does not necessarily indicate obstruction. A full bladder may also cause mild calyceal dilation due to ureteral reflux and repeat ultrasound with an empty bladder should be performed. Persistent or increasing hydronephrosis on repeat ultrasound examinations is highly suggestive of obstruction. A renal scan with furosemide washout may help support the diagnosis, but it does not provide clear anatomic detail. Although invasive, the placement of a percutaneous nephrostomy tube with an antegrade nephrostogram is the most effective way to visualize the collecting system and can be both diagnostic and therapeutic.
Blood clots, a technically poor reimplantation, and ureteral slough are common causes of early acute obstruction after transplantation. Ureteral fibrosis secondary to either ischemia or rejection can cause an intrinsic obstruction. The distal ureter close to the ureterovesical junction is particularly vulnerable to ischemic damage due to its remote location from the renal artery and hence its compromised blood supply. Ureteral fibrosis associated with polyoma BK virus is a newly recognized cause of ureteral obstruction in the setting of renal transplantation. Ureteral kinking, lymphocele, pelvic hematoma or abscess, and malignancy are potential causes of extrinsic obstruction. Calculi are uncommon causes of transplant ureteral obstruction.
Definitive treatment of ureteral obstruction due to ureteral strictures consists of either endourologic techniques or open surgery. Intrinsic ureteral scars can be treated effectively by endourologic techniques in an antegrade or retrograde approach. A stent is left indwelling to bypass the ureteral obstruction and can be removed cystoscopically after 2–6 weeks. Routine ureteral stent placement at the time of transplantation may be associated with a lower incidence of early postoperative obstruction. Extrinsic strictures or strictures that are longer than 2 cm are less likely to be amenable to percutaneous techniques and are more likely to require surgical treatment, as do strictures that fail endourologic incision. Obstructing calculi can be managed by endourologic techniques or by extracorporeal shock wave lithotripsy.
Despite the routine use of prophylactic therapy against common bacterial, viral, and opportunistic pathogens in the perioperative and postoperative period, infection remains an important cause of morbidity and mortality after organ transplantation. The time to occurrence of different infections in immunocompromised transplant recipients follows a “timetable” pattern.
In the first month after transplantation, infections are most frequently caused by bacterial microorganisms. Similar to those following any major surgical procedure, the sources of infection after solid organ transplantation include surgical wounds, surgical drainage catheters, an indwelling Foley catheter, bacteremia from vascular access devices, aspiration pneumonia, and urinary tract infections (UTIs). Potential sources of infection specific to renal transplant recipients include perinephric fluid collections due to lymphoceles, wound hematomas or urine leaks, indwelling urinary stents, and anatomic or functional genitourinary tract abnormalities such as ureteral stricture or vesicoureteric reflux and neurogenic bladder. Although bacterial pathogens may vary from center to center, UTIs in renal transplant recipients are commonly caused by Enterococcus spp., Enterobacteriaceae, and Pseudomonas aeruginosa. Preventive and prophylactic measures to reduce UTIs include early Foley catheter removal and antibiotic prophylaxis. The use of trimethoprim-sulfamethoxazole or ciprofloxacin prophylaxis effectively reduces the frequency of UTIs to less than 10% and essentially eliminates urosepsis unless urine flow is obstructed. Although strict aseptic surgical techniques and the perioperative use of the first generation cephalosporins reduce the incidence of wound infections, nonmodifiable risk factors include the presence of diabetes mellitus and obesity at the time of transplant. Weight reduction prior to transplantation should therefore be encouraged.
After the first posttransplant month, infections with immunomodulating viruses including cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein–Barr virus (EBV), hepatitis B virus (HBV), and hepatitis C virus (HCV) may occur either due to the overall state of immunosuppression, exogenous infection, or reactivation of latent disease. Repeated courses of antibiotics and corticosteroid therapy increase the risk of fungal infections whereas infections with immunomodulating viruses may render the patients more susceptible to opportunistic infections. Causative opportunistic agents include Pneumocystis jiroveci, Aspergillus spp., Listeria monocytogenes, Nocardia species, and Toxoplasma gondii. Trimethoprim prophylaxis eliminates P jiroveci pneumonia (PCP) and reduces the incidence of L monocytogenes meningitis, Nocardia spp. infection, and T gondii. Beyond 6 months following transplantation, the risk of infection in patients with good allograft function is similar to that of the general population, with community-acquired respiratory viruses constituting their major infective agents. These patients are usually maintained on a relatively low level of immunosuppression. In contrast, patients who experience multiple episodes of rejection requiring repeated exposure to heavy immunosuppression are the most likely candidates for chronic viral infections and superinfection with opportunistic organisms. Causative opportunistic pathogens include P jiroveci, L monocytogenes, N asteroides, and Crytococcus neoformans. Geographically, restricted mycoses include coccidioidomycosis, histoplasmosis, blastomycosis, and paracoccidioidomycosis. In high-risk candidates, lifelong prophylactic therapy has been advocated. Suggested prophylactic therapy in renal transplant recipients in shown in Table 53–12.
Table 53–12. Suggested Prophylactic Therapy for Recipients of Renal Transplants. ||Download (.pdf)
Table 53–12. Suggested Prophylactic Therapy for Recipients of Renal Transplants.
Its routine use reduces or eliminates the incidence of PCP, Listeria monocytogenes, Norcardia asteroides, and Toxoplasma gondii In renal transplant recipients, TMP/SMX reduces the incidences of UTI from 30–80% to less than 5–10%
Monthly intravenous or aerosolized pentamidine >dapsone1 >atovaquone
Replaces TMP/SMX for patients with sulfa allergies
Nystatin 100,000 U/mL, 4 mL qpc and qhs
For fungal prophylaxis
Acyclovir, valganciclovir, ganciclovir
For CMV prophylaxis see Table 53–12
CMV infection occurs primarily after the first month posttransplantation and continues to be a significant cause of morbidity the first 6 months after organ transplantation. CMV infection may occur in the setting of primary infection in a seronegative recipient (donor seropositive, recipientseronegative), reactivation of endogenous latent virus (donor seropositive or seronegative, recipient seropositive), or superinfection with a new virus in a seropositive recipient (donor seropositive, recipient seropositive). Primary CMV infection often results in more severe disease than reactivation or superinfection. The clinical manifestations of CMV infection span the spectrum of asymptomatic seroconversion, mononucleosis-like syndrome, or flu-like illness with fever and leukopenia, and/or thrombocytopenia to widespread tissue invasive disease. The latter may result in clinical hepatitis, esophagitis, gastroenteritis, colitis, pneumonia, and allograft dysfunction. Donor and recipient seropositive status and the use of blood products from CMV seropositive donors are well-established risk factors for CMV infection. Other factors associated with an increased risk of CMV infection include the use of antilymphocyte antibodies, prolonged or repeated courses of antilymphocyte preparations, episodes of allograft rejection, comorbid illnesses, and neutropenia. Management of CMV infection consists of preventive (prophylactic and/or preemptive therapy) and therapeutic measures. Prophylactic therapy involves antiviral therapy beginning in the immediate postoperative period whereas preemptive therapy involves treatment of those who are found to seroconvert during surveillance studies. Treatment of established CMV disease consists of 2–3 weeks of intravenous ganciclovir followed by a 2- to 4-month course of oral ganciclovir or valganciclovir. In patients slow to respond to therapy the addition of CMV hyperimmune globulin can be of therapeutic benefit. Although oral valganciclovir provides good bioavailability, its use in the treatment of CMV disease has not been well studied. A suggested CMV prophylaxis protocol is shown in Table 53–13.
Table 53–13. Cytomegalovirus (CMV) Prophylaxis Protocol.1 ||Download (.pdf)
Table 53–13. Cytomegalovirus (CMV) Prophylaxis Protocol.1
For CMV (−) recipients of a CMV (−) organ
Acyclovir 400 mg daily (or valganciclovir 450 mg daily) × 3 months
CMV DNA every 2 weeks × 3 months
For CMV (−) recipients of a CMV (+) organ
During antibody treatment DHPG2 2.5 mg/kg intravenously every day
Following antibody treatment valganciclovir 900 mg orally every day × 6 months
If no antibody treatment: valganciclovir 900 mg every day for 6 months
CMV DNA every 2 weeks × 3 months
For CMV (+) recipients of a CMV (−) organ
During antibody treatment DHPG 2.5 mg/kg intravenously every day
Following antibody treatment valganciclovir 900 mg orally every day × 6 months
If no antibody treatment: acyclovir 400 mg daily (or valganciclovir 450 mg daily) × 3 months
CMV DNA every 2 weeks × 3 months
For CMV (+) recipients of a CMV (+) organ
During antibody treatment DHPG 2.5 mg/kg intravenously every day
Following antibody treatment valganciclovir 900 mg orally every day × 6 months
If no antibody treatment: acyclovir 400 mg daily (or valganciclovir 450 mg daily)3 × 3 months
CMV DNA every 2 weeks × 3 months
Candida Fungal Infections
Candida spp. are the most common fungal pathogens encountered in the immunocompromised transplant recipients, with C albicans and C tropicalis accounting for 90% of the infections followed by C glabrata. Diabetes mellitus, high-dose corticosteroids, and broad spectrum antibacterial therapy predispose patients to mucocutaneous candidal infections such as oral candidiasis, intertriginous candidal infections, candidal esophagitis, candidal vaginitis, and candidal UTIs. Superficial infections involving the mouth or intertriginous areas can be treated with nystatin and topical chlortrimazole whereas candidal UTIs require amphotericin B bladder washing or systemic antifungal therapy with fluconazole, amphotericin B (preferably in the lipid preparation), or caspofungin for fluconazole-resistant species. Whenever possible, foreign objects such as a bladder catheter, surgical drains (such as a percutaneous nephrostomy tube), and urinary stents should be removed.
The polyomaviruses are nonenveloped double-stranded DNA viruses. BK and JC viruses are the two strains associated with disease in humans and are named after the initials of the patients in whom they were first isolated. Over the past decade BK virus-associated nephropathy has emerged as an important cause of allograft failure following renal transplantation, whereas the pathogenic role of JC virus in allograft nephropathy remains to be defined.
BK virus is a ubiquitous human virus with a peak incidence of primary infection in children 2–5 years of age and a seroprevalence rate of greater than 60–90% among the adult population worldwide. Following primary infection, the BK virus preferentially establishes latency within the genitourinary tract and frequently reactivates in the setting of immunosuppression. In renal transplant recipients, the BK virus has been shown to be associated with a range of clinical syndromes including asymptomatic viuria with or without viremia, ureteral stenosis and obstruction, interstitial nephritis, and BK allograft nephropathy. In most series it has been reported that 30–40% of renal transplant recipients develop BK viuria, 10–20% develop BK viremia, and 2–5% develop BK nephropathy (BKN).
BK nephropathy most commonly presents with an asymptomatic rise in serum creatinine between 2 and 60 months (median 9 months). The diagnosis of BKN is made by allograft biopsy showing BK virus inclusions in renal tubular and glomerular epithelial cells. Variable degrees of interstitial inflammation, degenerative changes in tubules, and focal tubulitis can be seen and may mimic acute tubular necrosis (ATN) or acute rejection. In the absence of classic histologic findings, distinguishing between BKN, acute rejection, and the concomitant presence of both processes can be a diagnostic challenge. Additional ancillary studies such as immunohistochemistry, in situ hybridization, or electron microscopy are required to confirm the diagnosis. Urine cytology for decoy cells or quantitative determinations of viuria and of viral load in blood have been proposed as surrogate markers for the diagnosis of BKN. In the late stage of BKN, few characteristic intranuclear inclusions are seen and the histopathologic changes are indistinguishable from those of chronic allograft nephropathy including interstitial fibrosis and scarring.
There has been no well-defined protocol for the treatment of BKN. The current mainstay of treatment includes a reduction or discontinuation of antimetabolites in conjunction with a judicious reduction in calcineurin inhibitor therapy or other components of the immunosuppressive regimen. The level of reduction in immunosuppression, however, has not been clearly defined. Switching from tacrolimus to cyclosporine or to sirolimus has resulted in resolution of BKN and viremia/viuria in anecdotal case reports. Adjunctive antiviral therapy with cidofovir or leflunomide has been used with variable response rates. Low-dose cidifovir (0.25–0.33 mg/kg intravenously biweekly) may be of therapeutic benefit in refractory cases. Despite various treatment strategies, up to 30–50% of patients with established BKN experienced a progressive decline in renal function and graft loss. Early diagnosis and intervention may improve the prognosis. Intensive monitoring of urine and serum for BK by polymerase chain reaction (PCR) during the first year posttransplantation and preemptive withdrawal of immunosuppression have been shown to be associated with resolution of viremia and an absence of BK nephropathy without acute rejection or graft loss. More recently, an independent panel of experts have suggested that all renal transplant recipients should be screened for BKV replication in the urine (1) every 3 months during the first 2 years posttransplant, (2) when allograft dysfunction is noted, and (3) when an allograft biopsy is performed. A positive screening result should be confirmed in <4 weeks and assessed by quantitative assays (eg, BKV DNA or RNA load in plasma or urine). A definitive diagnosis of BKN requires an allograft biopsy. In the absence of active viral replication, patients with graft loss due to BKN can safely undergo retransplantation. Active surveillance for BK virus reactivation after transplantation is recommended.
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