I N F ECTION AF TER KI DN EY TR AN SP L ANTATION

PREVALENCE OF INFECTION AFTER KIDNEY TRANSPLANTATION

Infection affects all kidney transplant recipients, in one form or another. Over 50 percent of transplant patients have at least one infection in the rst year following transplantation.88 And for those individuals lucky enough to make it through the rst year without an infectious complication, they will be indirectly affected too as they must take prophylactic medications. Infection is a much bigger issue for transplant recipients than for the general population. The potential seriousness of infection in the kidney transplant patient can be appreciated by comparing the hospitalization rate for septicemia in kidney transplant recipients with that of the general population. Abbott et al evaluated this and found that kidney transplant recipients have an adjusted incidence ratio of hospitalizations for septicemia of 41.52 (95 percent CI 35.45-48.96) compared to that of the general population.89 The risk of contracting any specic infection changes with the post-transplant time (Figure 3). Within the rst month post-transplant the debilitating effects of immunosuppression have not been realized and consequently more than 90 percent of infections are bacterial or from candida: the same types of infections that occur in the non-

immunosuppressed individual. For example in the rst month, patients are at risk for post-operative pneumonias, intravenous line related infections or those due to a faulty catheter. Occasionally there is a reemergence of a non-eradicated infection that the recipient carried or an infection that was transmitted with the transplanted kidney.90 In the one to six month time period, immunomodulating viruses are most problematic. Cytomegalovirus (CMV) is a prime example of such a virus.90 If the patients graft is working well more than six months post-transplant, and he or she did not require additional immunosuppression to combat rejection, he or she is primarily at risk for infections encountered by the general population such as pneumonias and urinary tract infections. A small group of patients may experience persistent viral infections such as CMV, Epstein-Barr virus (EBV) and hepatitis during this time period. Another small set of patients who received additional immunosuppression are at risk for opportunistic infections like cryptococcus, pneumocystis, listeria and nocardia.90 There are a multitude of potential infections that can affect transplant recipients. In lieu of listing all, this section will focus on several specic infections to consider.

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Figure 3.

Usual Sequence of Infections after Organ Transplantation 90

T R E A T M E N T S T R A T E G I E S N E W 27 F O R

CMV
Cytomegalovirus (CMV), a common post-transplant infection, remains one of the most important pathogens.90-93 As a herpes virus, CMV has the potential to exist in a cell-associated latent state. Infected individuals have the virus for their entire life.90 After transplant, patients can manifest CMV infection and disease either by reactivation of latent virus or transmitted infection. Transmission can

CMV can manifest either as an infection or as a disease. Infection is dened as seroconversion documented by anti-CMV IgM antibodies or a 4-fold increase in IgG titers or detection of the presence of CMV antigen or having positive viral cultures. Disease is infection plus clinical signs and symptoms such as fever, leukopenia, and/ or organ involvement.94 Disease severity can range the gamut from malaise to life threatening organ involvement.93, 95 One of the more serious manifestations is pneumonitis. Other potential organ involvement includes gastroenteritis, retinitis and nephritis.

A D V E R S E

E V E N T S

R E L A T E D

The Most Common Infections Associated with Kidney Transplantation

T H E

occur by the transplanted organ or less commonly from transfused blood products.

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CMV infection is classied as primary, reactivation or superinfection. Primary infection (affecting those individuals designated as D+R- for seropositive donor, seronegative recipient) occurs when latently infected cells from a seropositive donor are administered to a seronegative recipient. Reactivation [affecting those designated as R+

for seropositive recipient, irrespective of whether the donor is positive (D+) or negative (D-)] occurs when endogenous latent virus is reactivated, and superinfection (affecting individuals designated as D+R+) occurs when latently infected cells from a seropositive donor are administered to a seropositive recipient, and the recipient becomes

Table 5.

Diagnosis of CMV 91

Method
Histopathology

Source
Tissue

Comment
Detects inclusion bodies, very insensitive, requires biopsy. Several techniques available for detection of IgG and IgM. ELISA is most common, but others include complement fixation and latex agglutination. Useful to detect past exposure (IgG). Not useful for early diagnosis of acute infection. Failure to detect IgM in presence of viruria indicates a poor prognosis. Long development time (1 to 3 weeks). Subject to technical complications from cytotoxicity. Positive test indicates active CMV. Sensitivity decreased with a delay of processing exceeding 6 hours. Necessary for plaque assay resistance testing. Rapid development time (1 to 2 days). Semiquantifiable. Less labor intensive than antigenemia assay. Positive test indicates active CMV. Sensitivity decreased drastically with a delay of processing exceeding 6 hours. Rapid (same day). Semiquantifiable. Labor intensive, requires specially trained technician. Sensitivity decreased with a delay of processing exceeding 6 hours. Fairly rapid (same day), can be batched. Most sensitive of all tests. Positive test indicates active CMV but not necessarily symptomatic CMV (latent CMV rarely detectable). Allows quantification. PCR of DNA is not adversely affected by delays in transportation. Rapid. Detects viral DNA, less sensitive than PCR. Quantifiable. Less sensitive. Reproducible. Detects viral RNA, highly sensitive. Requires special techniques, may localize CMV DNA.

Serology

Serum

Conventional tube culture

Any

Shell vial assay

Any

Antigenemia assay

Blood

PCR and PCR taqMan

E

Any

Hybrid capture assay Branched DNA NASBA In situ DNA hybridization

Any Any Any Tissue

Abbreviations: CMV, cytomegalovirus; ELISA, enzyme-linked immunosorbent assay; NASBA, nucleic acid sequence-based amplication.

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T H E S T R A T E G I E S N E W 29 F O R

A D V E R S E

Once a patient has CMV disease, IV ganciclovir is the rst line therapy; though theoretically oral valganciclovir treatment may be effective.94 Whether or not polyvalent IVIG or CMVIG adds any additional benet to this regimen is unclear.94 In cases of ganciclovir-resistant CMV, foscarnet should be considered (with or without ganciclovir). Cidofovir may also have a role in this setting.

HCV rates are higher in dialysis patients than in the general population.98 The rates vary with geographical location97, 98 and have been reported as: Northern European countries, less than ve percent; UK and New Zealand, between three and ve percent, U.S., between 10 and 20 percent; Mediterranean countries, greater than 20 percent.98

E V E N T S

R E L A T E D

Effective antiviral agents for CMV prophylaxis and treatment have markedly decreased the morbidity and mortality of CMV disease. Current guidelines recommend three months of prophylactic therapy (oral ganciclovir, valganciclovir, valacyclovir or IV ganciclovir) for those who are D+/R-.94 In those who are R+, recommended prophylaxis includes three months of oral ganciclovir, valganciclovir or valacylovir.94

P R E V E N T I O N

The main route of infection is parenteral: IV drug abuse or blood products. Transmission is also possible through organ transplantation, tattoos, needle stick accidents, and sexual contact (rare in heterosexual, high risk in homosexual relationships).98 Diagnosis can be made through serological assays evaluating the presence of antibodies against HCV antigens, assays detecting and quantifying HCV antigens, or assays detecting and quantifying HCV genomes and analyzing their base pairs. Liver function tests as a means of diagnosis are not helpful: 25 percent of those with HCV may have normal ALT.98

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A N D

CMV can be diagnosed in variety of ways including various culture techniques, serology, detection of CMV antigens, and by polymerase chain reaction (PCR) as outlined in Table 5.

T R E A T M E N T

T H E R A P Y

infected with the donors CMV. The risk of infection and disease varies with the serostatus of the donor and recipient, those who are in the D+/R- are at greatest risk for infection as well as the most acutely symptomatic illness.95 And though primary infection remains a concern due to its potential for the acute CMV illness in its most severe form, indirect effects are also a concern. For example work done by Brennan et al has shown that at three years, those in the D+/R+ group (not D+/R) have the worst graft and patient survival.91 In another study CMV infection as well as disease were independent risk factors for allograft rejection, new-onset diabetes mellitus, and in the long-term (beyond 100 days) for recipient mortality and graft loss.96

HCV: A RELATIVELY COMMON INFECTION ASSOCIATED WITH KIDNEY TRANSPLANTATION

Hepatitis C virus (HCV) is a small (30-36 nm in diameter) lipoid-enveloped, single stranded RNA. It is a member of the Flaviviridae family (that includes yellow fever, dengue virus, and Pestivirus).97 There are at least six main genotypes: types 1 to 6 and subtypes a, b, and c.98 The outcome of HCV disease in the general population and response to antiviral therapy correlates with HCV type.98 Genotype 1 (1b in particular) has been associated with more severe chronic liver disease and has a poorer response to interferon (IFN).98 The prevalence of different HCV genotypes in kidney transplant recipients reects the prevalence of HCV genotypes in the general population with chronic hepatitis.

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Figure 4.

Survival of HCV-positive renal failure patients 99

Group I patients (transplant recipients) had a better survival than group II patients (acceptable candidates, not yet transplanted) (P = 0.043 by the log-rank test).99

When considering whether patients with HCV should undergo transplantation it is important to recognize that in some,99,100 but not all studies,101,102 the presence of HCV prior to transplant has been associated with increased mortality after transplant. However, patients with end stage renal disease (ESRD) and HCV have an increased risk of death, whether they undergo transplantation or remain on dialysis.103 In counseling patients with HCV about the options for kidney replacement therapy, it is important to communicate that transplanted HCV patients have a lower mortality rate than those with HCV who remain on dialysis.99,103 (Figure 4) The post-transplant prognosis is as good for those with HCV as it is for uninfected patients at rst, however in the long run (after the rst decade) this group does not fare as well as those who do not have HCV (Figure 5).104 Cosio et al found a higher incidence of chronic vascular rejection in those with HCV.105

HCV infection is now recognized as a risk factor for new-onset diabetes after transplantation (NODAT).106,107 The mechanism for the connection between HCV and NODAT is unknown. This association is a concern for a number of reasons. One of this reasons is that NODAT has been shown to increase the risk of graft failure and death after transplant.108 Antiviral therapy for hepatitis C is not well tolerated and/or associated with graft dysfunction after transplant.109 Kidney transplant candidates with HCV should be referred for hepatology evaluation and considered for anti-viral treatment prior to transplantation.

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Figure 5.

Kaplan-Meier estimate of the cumulative probability of liver dysfunction (A), graft survival (B), patient survival (C) among recipients who are HCV-positive and HCV-negative. 104

T R E A T M E N T T H E S T R A T E G I E S N E W 31 F O R

BK Virus BK virus (BKV) is a human polyomavirus, 30-45 nm in diameter, with a nonenveloped icosahedral capsid.110, 111 These viruses have 5,300 base pair genomes arranged as superhelical double-stranded circular DNA.110 Polyomaviruses are species specic. There are two human species: BK virus (hominis 1) and JC virus (hominis 2). Most cases of Polyoma virus nephropathy (PVN) are due to BKV.112 There is an exception however to the two human species rule. In the late 1950s and early 1960s, millions were exposed to simian virus 40 (SV40) of

Most people are exposed to BK virus during childhood and 75-80 percent of adults have antibodies.115 The primary infection occurs at four to ve years of age and manifests as a subclinical

A D V E R S E

After the rst reported case in 1971, the diagnosis more or less disappeared but reemerged as a problem in 1995. Since that time, there has been a stepwise increase in BKV from one percent in 1995 to ve percent in 2001.114

E V E N T S

R E L A T E D

EMERGING INFECTIONS ASSOCIATED WITH KIDNEY TRANSPLANTATION

rhesus macaques through vaccinations with polio virus that were grown in contaminated cells.113 BK virus was rst recognized in 1971 after it was isolated from the urine of a Sudanese kidney transplant patient, who was hospitalized with acute renal failure and ureteral stenosis. The virus was named for the patient whose initials were BK.112

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Figure 6.

Graft survival analysis. Comparison between patients with polyomavirus nephropathy and controls (P = 0.004). 119

BK: 67 patients with graft dysfunction and PV in biopsy and urine; mean follow-up, 26 mo. Control: 162 patients with graft dysfunction and no evidence of PV in biopsy and urine; mean follow-up, 25.3 mo.119

or nonspecic u-like illness.116, 117 Human polyomaviruses then establish latency primarily in the renourinary tract.116 Viral reactivation generally occurs in the immunocompromised patients though reactivation and urinary shedding has occasionally been documented in immuno-competent individuals.110 Kidney transplant patients can become infected through reactivation of latent virus or primary infection transmitted from the donor organ or blood transfusion.112 BK virus is believed to transition from viruria to viremia to nephropathy.118 Why this escalation occurs is unknown. Though generally seen in kidney transplant patients, BK nephropathy has also been documented in native kidneys.117 Although specic risk factors for nephropathy have not been unequivocally identied, BK seems to be a result of too much immunosuppression. When nephropathy occurs, if left unstopped it is associated with a poor prognosis (Figure 6).119 Treatment options include reduction of immunosuppression and antiviral agents (including

cidofovir and leunomide).120 Centers use these approaches, though none have been rigorously tested for efcacy. Cidofovir is currently undergoing a multi-center study. Given the lack of proven effective treatment and the nding that the more advanced the kidney lesion is at the time of diagnosis, the worse the prognosis,121 experts advocate screening for the presence of the virus prior to the onset of kidney dysfunction.114 Several screening approaches have been described including decoy cell detection in the urine, PCR for virus in the urine, and PCR for virus in the blood.114 BK is an emerging virus and one for which there remain many dilemmas, including whether to and how to screen, how to treat, and whether to perform a repeat transplant if a patient loses his or her kidney allograft to BK nephropathy. One thing though that is not a dilemma, is that BK is a potentially very serious problem and if left to progress BK will lead to graft loss.119, 122

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NURSING PERSPECTIVE ON INFECTION AFTER KIDNEY TRANSPLANTATION

The key to effective treatment of infection is invoking strategies for the prevention and early identication of new infections. An important part of nursing care for KTR is identifying the pre-transplant serological status of the KTR and the serologies of the donor to identify those patients at higher risk for opportunistic infections and educate patients regarding their particular risk factors. This includes the types of infections they are at risk for during each post-transplant phase. General guidelines for

prevention of infection are shown in Table 6. It is important to stress the need for compliance with prophylaxis. Understanding the rationale for the drug regimen may increase adherence. Patients need to be educated regarding how to identify signs and symptoms of infection and when to call the transplant team. Since many KTR return to the community for general health maintenance, it is important that they are taught to call the transplant team prior to starting any new medications. Many antibiotics are nephrotoxic or alter immunosuppression levels and should be avoided.

T R E A T M E N T P R E V E N T I O N T H E S T R A T E G I E S N E W 33 F O R A N D

Table 6.

Critical elements for patient education regarding infection

Wash hands often. Notify the transplant team of temperature, signs and symptoms of infection. Notify the transplant team before starting antibiotics prescribed by clinicians, who are not part of the transplant team. Complete all courses of antibiotics. Avoid people with colds and infections. Avoid handling animal waste and contact with animals that roam outside. Do not change the bird cage or the cat litter. Wear gloves when gardening. Keep vaccinations up to date. Avoid live vaccines, and if family members receive live vaccines, notify the transplant team. Consider food safety. Avoid raw meats and fish. Eggs should be eaten cooked. Wash fruits and vegetables well. Drink bottled water when traveling outside the United States. Thoroughly clean countertops.

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O F