Infectious Complications of Kidney Transplantation

Introduction:

Infections that develop after transplantation may be life-threatening and may affect outcomes. Infection follows cardiovascular disease as the second most common cause of death with a functioning graft in kidney transplant recipients. Post-transplant infections develop in approximately 40% of recipients within the first year in spite of prophylaxis.

Both the type and occurrence of infections in the immunocompromised transplant recipient follow a timetable pattern.

HBV, hepatitis B virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; LCMV, lymphocytic choriomeningitis virus; MRSA, methicillin-resistant Staphylococcus aureus; PCP, Pneumocystis carinii pneumonia; PML, progressive multifocal leucoencephalopathy; PTLD, post-transplantation lymphoproliferative disorder; SARS, severe acute respiratory syndrome; VRE, vancomycin-resistant Enterococcus faecalis; VZV, varicella-zoster virus. Reproduced from Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007; 357:2601-14. With permission from the Massachusetts Medical Society. © 2007 Massachusetts Medical Society.

Risk Factors for Posttransplant Infectious Complications

1. Pretransplant host factors:
   • Underlying medical condition e.g. Diabetes Mellitus
   • Chronic infections e.g. Hepatitis C viral infection
   • Latent infections e.g. Tuberculosis, Dimorphic fungi
   • Colonization with resistant bacteria
   • Recipients preexisting immunity e.g. Varicella Zoster Virus
   • Prior medications e.g. Antimicrobials, Corticosteroids
2. Transplant factors:
   • Allograft derived e.g. Cytomegalovirus
   • Surgical duration, instrumentation, wound, abdominal fluid collections, technical issue e.g. type of anastomosis
   • Blood transfusion
3. Immunosuppression
   • Immunosuppressive agents and additional treatment for episodes of rejection
4. Time posttransplant
5. Epidemiologic exposure

Urinary Tract Infections:

Urinary tract infections (UTIs) are the most common bacterial infections following transplantation, which develop in approximately 20% of recipients.

Female sex, genitourinary tract manipulation during transplantation, prolonged bladder catheterization, ureteric stenting, age, and delayed graft function (DGF) are independent risk factors. UTIs are independently associated with the development of bacteremia, and untreated UTIs are associated with subsequent rejection (3). Post-transplant vesicoureteric reflux occurs in up to 40% of transplant recipients, although is not associated with the UTI risk (4).

Ureteric stents mitigate the risk of ureteric strictures and leaks after transplantation. Center practices vary, with stenting of all patients at some centers and more selective stenting at others. Wilson et al. performed a Cochrane analysis of seven randomized controlled trials (RCTs) encompassing 1,154 patients that examined the practice of allograft ureteric stenting (5). The incidence of major urologic complications including urine leak and obstruction was significantly reduced (relative risk [RR], 0.24; 95% CI, 0.07 to 0.77; P=0.02; number needed to treat = 13) by universal prophylactic stenting. However, UTIs were more common in stented patients (RR, 1.49; 95% CI, 1.04 to 2.15), unless the patients were prescribed trimethoprim/sulfamethoxazole (TMP/SMX), in which case the incidence was equivalent (RR, 0.97; 95% CI, 0.71 to 1.33). Stents were generally well tolerated, although studies using longer stents (≥20 cm) for longer periods (> 6 weeks) developed problems more frequently with encrustation and migration.

Typical pathogens include Escherichia coli, Klebsiella, Proteus, Enterococcus, Enterobacter, Staphylococcus, and Pseudomonas. In the case of recurrent infections, abscesses or other nidi of infection should be sought out by means of imaging with ultrasound or computed tomography. Early catheter removal decreases the incidence of UTI in renal allograft recipients. The use of TMP/SMX to prevent Pneumocystis jirovecii pneumonia and UTI has long been the standard of care after kidney transplantation. Wojciechowski et al. performed a single-center study comparing TMP/SMX for 6 months (group 1) versus TMP/SMX for 6 months plus ciprofloxacin for 30 days (group 2) for prophylaxis after kidney transplantation (6). At 1 year, more patients in group 1 developed UTIs (23.6% versus 10.8%; P=0.01) and the mean time to first UTI was shorter. There was a similar incidence of enteric Gram-negative antibiotic resistance to TMP/ SMX (75% versus 80%; P=1.00) and ciprofloxacin (16.7% versus 30%; P=0.39) in groups 1 and 2. For groups 1 and 2, the proportion of first UTIs requiring hospitalization was 48.9% versus 40.6%, respectively.

A clean-catch midstream urine specimen should be submitted for quantitative bacterial and fungal culture. Antibiotic therapy should be tailored according to the offending microorganism and drug susceptibility tests.

Septicemia:

The incidence of hospitalizations for septicemia among renal transplant recipients is approximately 42 times that of the general population. The urinary tract is the most common source of septicemia, followed by the lungs, the surgical wound site, and the abdomen. Most cases occur within the first six months after transplantation. Among patients with bacteremia, poor outcome is associated with Gram-negative species, multidrug-resistant organisms, and Candida species, especially when the empiric antimicrobial therapy is inappropriate or delayed.

Bige et al. retrospectively studied 83 kidney transplant recipients (KTRs) admitted for sepsis, severe sepsis, or septic shock to their intensive care unit over a 10-year period (1). The main sites of infection were the lung (54%), urinary tract (24%), and bloodstream (22%). Eighty percent of infections were bacterial. Mechanical ventilation was used in 46 patients (56%), vasopressors in 39 patients (47%), and RRT in 34 patients (41%). The 90-day mortality rate was 22%. By day 90, among the 65 survivors, 39 (47%) had recovered their previous graft function, and 26 (31%) had impaired graft function, including 16 (19%) who were dependent on RRT.

Some studies suggest that bacterial sepsis increases the risk for CMV infection because of high levels of tumor necrosis factor-α (TNF-α) or dysregulated immune response to CMV in the context of serious bacterial infections. For detection of bloodstream infection, two sets of blood cultures should be obtained before initiation of antimicrobial therapy. If intravascular catheter-associated bacteremia is suspected, the device should be removed and the catheter tip should be cultured.

Pneumonia:

The incidence of pneumonia in kidney transplantation is the lowest among all solid organ transplants (8 to 16 percent). However, pneumonia is the most serious infection, leading to death in up to 50 percent of cases. The infectious agent in the majority of patients is never determined. This is likely because of the low yield of blood and sputum cultures and the efficacy of antibacterial therapy. In patients who are hypoxic on presentation or do not respond to initial therapy, a bronchoscopy and bronchoalveolar lavage (BAL) is almost always warranted.

Patients should be referred if possible to a transplant center to improve the likelihood of diagnosing the etiologic agent. Common causative organisms include Streptococcus pneumoniae, nontypable Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae, Mycoplasma pneumoniae, and respiratory viruses such as influenza, adenovirus, and respiratory syncytial virus (RSV).

Less commonly, patients may present with opportunistic organisms such as P. jirovecii and L. pneumophila. Silver stains for direct fluorescent antibody for Pneumocystis should be done on sputum or BAL specimens. A urine Legionella antigen test should be done on all patients on initial work up.

Mycobaterium tuberculosis:

Among the infections, tuberculosis is an important cause of morbidity in renal transplant recipients in developing world. The incidence of post-transplant tuberculosis in India has been reported to be highest in the world at 5.7 to 10 percent in various studies. Most cases of Mycobacterium tuberculosis infection in kidney transplant recipients are due to reactivation of latent tuberculosis lesions. Important risk factors for reactivation include nonwhite race, history of active tuberculosis, presence of marked abnormality on a chest radiograph, exposure to person with a confirmed case of tuberculosis, and skin test positivity. In transplant patients, the clinical presentation of tuberculosis may be atypical and extrapulmonary and miliary tuberculosis is seen more frequently than in the normal population.

Tuberculosis presents numerous diagnostic difficulties in renal transplant recipients. Because of high frequency of anergy in immunosupressed patients, the Mantoux test is generally unhelpful as a diagnostic tool. e classic picture of apical involvement in the general chest X-ray is seen in only a minority of renal transplant recipients with pulmonary tuberculosis. Demonstration of acid-fast bacilli in the sputum smear requires repeated examination on several occasions and has a low yield. Identification on culture takes four to six weeks.

Treatment of post-transplant tuberculosis presents problems both in the choice of antitubercular agents and in the duration of therapy. Rifampicin is a well-known hepatic P-450 microsomal enzyme inducer, increasing the clearance of both prednisolone and cyclosporine A. The dose of prednisolone needs to be doubled and that of cyclosporine increased to three- to four-fold to maintain therapeutic blood levels. e latter increases the cost of therapy and is unacceptable to a vast majority of patients. An alternative regime that has been successfully used for these patients consists of a combination of isoniazid, pyrazinamide, ofloxacin, and ethambutol. e optimum duration of therapy is also a matter of debate but is usually for 9 to 12 months. e duration needs to be increased to 18 months in patients who are on cyclosporine and are not receiving rifampicin. e role of INH prophylaxis after transplant in endemic areas is controversial.

Cytomegalovirus (CMV):

CMV is a significant cause of morbidity and mortality among kidney transplant recipients. Between 60 and 90 percent of adults are seropositive. Symptomatic disease ranges from a relatively mild syndrome of fever, leukopenia, thrombocytopenia, and elevated liver enzymes to severe disseminated disease that involves multiple organ systems, such as the lung, liver, and GI tract. CMV disease has been implicated as a cause of acute and chronic graft dysfunction as well as long-term graft loss. CMV can also suppress the immune response which predisposes the host to infections with other viruses, bacteria, and fungi.

The incidence and severity of CMV disease has been most strongly associated with the CMV serostatus of the kidney donor and recipient. Seronegative recipients who receive a kidney from a seropositive donor (D+/R-) are at greatest risk for severe primary infection during the first three months’ post-transplant. Rapid and accurate diagnosis of CMV is important because delayed recognition results in increased morbidity. Quantitative real-time polymerase chain reaction assays for CMV DNA and pp65 antigen detections are the most commonly used means to detect CMV viremia. e shell vial viral culture method remains a reliable way of detecting CMV in sputum.

Multiple strategies have been used to reduce the morbidity and mortality of CMV infection and its associated costs (see Table 4). Avoiding CMV sero- mismatching through organ allocation is not feasible or worthwhile. Universal prophylaxis refers to giving prophylactic therapy to all kidney transplant patients regardless of their CMV serostatus. Selected prophylaxis refers to giving prophylaxis to patients at high risk for CMV, namely the D+/R- category or those receiving lymphocyte-depleting therapy. e preemptive treatment approach treats asymptomatic CMV infection in an e ort to prevent CMV disease. Each approach has its advantages and disadvantages, and there is no de nitive consensus on optimal preventive strategy.

Prophylactic Therapy:

Prophylactic therapy is effective in preventing CMV disease in high-risk patients. Ganciclovir and valganciclovir are equally efficacious. Ganciclovir 1,000 mg PO three times daily and valganciclovir 900 mg PO once daily are used. Valganciclovir is contraindicated in patients with a creatinine clearance of less than 10 ml/h. Prophylactic therapy is usually given during the first 100 days post- kidney transplant. A concern with the prophylactic strategy is that 20 to 30 percent of high-risk patients go on to develop late-onset CMV disease after the prophylaxis is stopped, and the incidence of ganciclovir resistance may be higher in those who receive prophylaxis.

Preemptive Therapy:

Preemptive therapy of CMV infection involves monitoring for CMV viremia and starting treatment before the development of signs or symptoms of disease. It has been shown to be as effective as prophylactic therapy in preventing CMV disease. Both oral ganciclovir and valganciclovir have been shown to be effective in treating viremia. Preemptive therapy has the advantage of avoiding the costs and complications of antiviral therapy in low-risk patients while at the same time initiating treatment early to avoid symptomatic disease in high-risk patients. It has also been shown to decrease the development of late CMV disease. Its major limitation is the need to perform frequent determinations of CMV viremia.

Ganciclovir Resistance:

Ganciclovir resistance is becoming more common among solid-organ transplant recipients. In one study, 6.2 percent of CMV isolates had UL97 or UL54 mutations. Viral strains with mutations in the UL97 gene, which encodes for a viral protein kinase, remain susceptible to foscarnet and cidofovir. Mutations in the UL54 gene that encodes DNA polymerase can result in resistance to ganciclovir, foscarnet, and cidofovir. e emergence of ganciclovir-resistant CMV underscores the importance of optimizing preventive strategies.

BK Virus (BKV):

BKV is associated with post-transplantation nephropathy, hemorrhagic cystitis, and ureteral obstruction. It has a tropism for genitourinary tract and usually remains dormant in the urinary tract and circulating leukocytes after the primary childhood infection and becomes reactivated during immunosuppression. Adult seroprevalence rates for BKV range from 65 to 90 percent and BKV reactivation can come from the recipient or the donor. BK viremia occurs in 13 percent and BK nephropathy in 8 percent of kidney transplant recipients. Analysis of risk factors for reactivation has underscored the central role played by serologic status of the donor, immunosuppressive regimens, injury to the uroepithelial tissue, and acute rejection. Distinguishing between BK infection and allograft rejection is of paramount importance, since BK infection necessitates reducing immunosuppression and allograft rejection requires the opposite.

Among kidney transplant recipients who are receiving immunosuppressive therapy, 10 to 60 percent have reactivation of BKV accompanied by shedding of urothelial cells. Shedding is inconsistently associated with allograft dysfunction. Once the virus has reactivated, an ascending infection via cell-to-cell spread occurs. e overall state of immunosuppression is the primary determinant of BKV reactivation. Viral replication begins early after transplantation and progresses through detectable stages-viruria, then viremia, then nephropathy. Viruria can be detected by PCR for BKV DNA, reverse transcription (RT)-PCR for BKV RNA, cytology for BKV inclusion bearing epithelial cells termed “decoy cells,” or electron microscopy for viral particles. Viremia is a better predictor of nephropathy than viruria. Although higher levels of viremia correlate with the risk of developing nephropathy, there are no established thresholds of viremia to indicate nephropathy.

The gold standard for establishing BK nephropathy remains a kidney biopsy with positive immuno- histochemical or immunofluorescent staining for the SV-40 large T antigen. An effective screening strategy is to check blood for BKV DNA by PCR monthly for the first 3 months and at 6 and 12 months after transplantation, at the time of any unexplained rise in serum creatinine, and after augmentation of immunosuppression. Because BKV nephropathy is preceded by BK viremia, asymptomatic BK viremia should prompt empiric immunosuppression reduction and continued monitoring.

Currently, no established antiviral treatment is available, and control of viral infection is tentatively obtained by means of reduction of immunosuppression. Treatment attempts have included immunoglobulins without proof of efficacy. Other options include deoxyspergualin, cidofovir, leflunomide, uoroquinolones and gyrase inhibitors. Cidofovir use is limited by its nephrotoxicity.

Fungal Infections:

The incidence of fungal infections in renal transplant recipients is less than that reported for other solid organ transplant recipients, the mortality from fungal infections remains high and is related to the pathogenicity of the organisms, site of infection, impaired host inflammatory response, limited diagnostic tools, potential for rapid clinical progression, failure to recognize a high-risk patient, and comorbidities, such as renal failure and diabetes mellitus.

Colonization with yeasts and molds occurs frequently in transplant candidates with ESRD and after transplantation because of exposure to broad-spectrum antibacterial agents, domiciliary and hospital exposures, immunosuppressive therapy, especially corticosteroids, and the presence of urinary catheters and endotracheal tubes. Isolation of Candida species from cultures of stool, respiratory, and urine samples occurs commonly in kidney transplant recipients receiving corticosteroids and broad-spectrum antimicrobials and does not necessarily imply infection. However, repeatedly positive fungal cultures from a single or from multiple sites may herald invasive candidiasis in the appropriate clinical setting.

Candida species, Aspergillus species, P. jiroveci, and C. neoformans are the most common fungal pathogens reported in renal transplant recipients.

Candida infections occur most commonly during the first month following transplantation and are usually associated with transplant surgical technical complications, early rejection, and enhanced immuno- suppression. Candida infection is most commonly associated with an endogenous source of colonization. C. albicans is the most common species, followed by C. glabrata, C. tropicalis, and C. parapsilosis. Speciation is clinically useful because nonalbicans Candida species vary in in vitro susceptibility to amphotericin B and azoles. Sites of Candida infection include mucocutaneous candidiasis and esophagitis; wound infections; cystitis, pyelonephritis, and ureteral obstruction by Candida elements or “fungal ball”; intra- abdominal infections, including infected perigraft fluid collections or peritonitis; and intravascular device- associated fungemia. Renal parenchymal infection most often results from candidemia and hematogenous spread, although ascending infection from the bladder can occur. Candiduria is typically asymptomatic but may be associated with cystitis or upper tract infection. Patients with genitourinary tract stents and recurrent funguria often require removal of foreign body to eradicate the infection.

Cryptococcus often presents as meningitis but may cause space-occupying brain lesions; pulmonary, dermatologic, skeletal, organ-specific disease; aspergillosis-pneumonia and other tissue-invasive forms, including genitourinary, central nervous system, rhinocerebral, GI, skin, wound, and musculoskeletal disease. Patients at risk for aspergillosis include those receiving repeated courses of enhanced immuno- suppression for rejection and those with chronic graft dysfunction, diabetes, comorbid medical illnesses, or CMV infection. Diagnosis of aspergillus infection depends on a high clinical suspicion, isolation of Aspergillus species from a sterile body site or repeated isolation from the respiratory tract, and typical radiographic findings. Radiologic appearances of pulmonary aspergillosis in kidney transplant recipients include nodules, di use or wedge-shaped opacities, empyema, or cavitary forms. Serial measurement of aspergillus galactomannan in the serum may aid in the early diagnosis of invasive aspergillosis in the high-risk setting.

Historically, invasive candidiasis, cryptococcosis, coccidioidomycosis, histoplasmosis, and aspergillosis were treated with amphotericin B deoxycholate (AmB). The lipid formulations of amphotericin B are all associated with lower risks for nephrotoxicity, metabolic derangements, and infusion-associated side effects than is AmB. Higher therapeutic dosages can be administered, and broad-spectrum antifungal activity is generally maintained.

Voriconazole appears to be superior to conventional AmB for the treatment of invasive aspergillosis and also has in vitro activity against a wider range of organisms. Available in both intravenous and oral formulations, the drug is generally well-tolerated, but some patients experience visual hallucinations or severe photosensitivity. Oral posaconazole has excellent activity in vitro against Candida, Aspergillus, and Mucor species, but experience in solid organ transplant recipients is limited to date. Although itraconazole has good in vitro activity against Aspergillus species, its use is generally reserved for treatment of less-severe aspergillosis or maintenance therapy following initial response to lipid amphotericin or voriconazole and for treatment of endemic mycoses. Fluconazole is the first-line agent of the treatment or prevention of reactivation of coccidioidomycosis in renal transplant recipients. The echinocandins, including caspofungin, anidulafungin, and micafungin, inhibit synthesis of fungal cell wall protein β1-3 glucan and are fungicidal for Candida species, including fluconazole-resistant species. Available only as intravenous formulations, the echinocandins are effective, well tolerated, and have few drug-drug interactions.