Updated principles and clinical caveats in the management of infection in renal transplant recipients

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Abstract

Renal transplantation is now considered the treatment of choice for patients with end-stage renal disease. In transplant recipients, infection and rejection are entwined and are unavoidable tribulations unless clinical tolerance becomes a reality. Although rejection rates have significantly decreased with the introduction of newer immunosuppressive agents, infections remain a major cause of morbidity and mortality, and the magnitude of the problem is on the rise. Newer infections are emerging and patterns of known infections are changing. The continuous evolution of donor and recipient characteristics also alters the landscape of infections. In clinical practice, establishing a definite diagnosis of infection in a timely manner remains a challenge in transplant recipients as compared to immunocompetent individuals. Hence a comprehensive knowledge of the principles of management of infections in renal transplant recipients is very essential. In this review, we would like to provide an overview of some of the key principles that we believe are essential in the management of infectious complications in renal transplant recipients with no focus on any individual infection.

Introduction

Renal transplantation is considered the treatment of choice for patients with end-stage renal disease because of better quality of life and increased longevity when compared to dialysis. The present 1-year patient and graft survival after renal transplantation are 95% to 97% and 89% to 95%, respectively [1]. This remarkable success is due to advances in surgical techniques, postoperative care, and targeted immunosuppressive therapy. Despite these strides, infectious diseases remain a major source of morbidity and mortality after transplantation. The risk of infection after renal transplantation is a complex function of the net state or degree of immunosuppression and of the epidemiology of infection (Fig. 1). Although rejection rates have declined significantly with newer immunosuppressive medications, the long-term graft survival rate has not improved significantly as one would expect [2]. Noticeably, this lack of long-term improvement coincides with infections such as cytomegalovirus infection (CMV), BK virus, and Epstein-Barr virus (EBV)–associated postlymphoproliferative disorders. In addition to these specific infections, a significant increase in all categories of infections has been documented in renal transplant recipients in recent years [3]. Overall, infections occur in 50% to 75% of transplant recipients during the first year posttransplantation, resulting in substantial direct and indirect consequences. Table 1 shows the types of infections by recipient age limited to the first year after renal transplantation [3]. Infections significantly contribute to poor patient and graft survival, prolonged hospital stay, increased cost of care, and the risk of malignancy [4]. In general, infectious complication accounts for 26% of recipient death with functioning graft and it is more pronounced in the elderly [3], [4]. In addition, infection can also contribute to death-censored graft loss from infections such as pyelonephritis, interstitial nephritis (BK virus or CMV), and from sepsis-related acute tubular necrosis. Rejection after withdrawal or minimization of immunosuppression for severe life-threatening systemic infections adds to further graft loss, and the total impact of infection on death-censored graft loss is not fully determined. Our own United Network for Organ Sharing data analysis presented at the American Transplant Congress in 2008 showed that the rate of death-censored graft loss has doubled in the last decade and correlates inversely with the rejection rate. Hence, a comprehensive knowledge of prevention and treatment of infectious complications in renal transplant recipients is imperative for physicians involved in the care of renal transplant recipients. We believe infection rates are an important quality measure of posttransplant outcomes.

All strategies to prevent or minimize the deleterious consequences of infection are essential for successful renal transplantation outcome. The following are the 8 key principles discussed in this review that may provide a conceptual framework in the management of infectious complications post renal transplantation.

  • 1.

    Pretransplant measures to decrease posttransplant infections

  • 2.

    Significance of time posttransplantation and the type of infection

  • 3.

    Major risk factors for infection and the net state of immunosuppression

  • 4.

    Disparity between severity of infection and clinical symptoms

  • 5.

    Drug interactions between antimicrobial agents and immunosuppressive drugs

  • 6.

    Changing patterns and emergence of newer infections

  • 7.

    Safe living after transplantation

  • 8.

    Immune monitoring and reconstitution of immune system in serious infections

Section snippets

Key principle 1: Pretransplant measures to decrease posttransplant infections

Prevention of infection can significantly decrease the morbidity and mortality posttransplantation; hence pretransplant measures are extremely important and they can be divided into 3 categories

  • 1.

    Identification and/or eradication of infections in potential recipients

  • 2.

    Screening of donors for transmissible infections and its avoidance

  • 3.

    Evaluation of the potential recipients for infections that require prophylaxis or preemptive therapy

Key principle 2: Timing of infections posttransplantation

Knowledge of different types of infection at different periods posttransplantation is essential to prioritize the evaluation process to identify the etiologic agent and the source of infection, and to facilitate selection of appropriate antimicrobial therapy. Although the calendar of events is constantly changing with the introduction of newer immunosuppressive agents and antimicrobial prophylaxis, the pattern of posttransplant infections generally is still reasonably predictable. The sequence

Key principle 3: The major risk factors for infection posttransplantation

The major risks for clinical infection in transplant recipients are a complex interaction between the epidemiological exposure to infective pathogens and the host's net state of immunosuppression [14], [15], [16]. The net state of immunosuppression is a dynamic interplay of immune regulatory responses that are affected by many factors such as immunosuppressive drugs, genetic background, sex, age, nutritional status, breaks in the mucocutaneous barrier, immunodeficiency disorders, persistent

Key principle 4: Drug interaction between antimicrobial and immunosuppressive agents

An important aspect of managing posttransplant infections is awareness of potential drug interactions between immunosuppressive medications and the antimicrobial agents. The optimal outcome of management of any infection depends not only on the knowledge of the infecting organism and the antimicrobial sensitivity, but also on the prevention of adverse events from severe drug interactions and allograft dysfunction that results from drug interaction. Generally, drug interactions can be grouped

Key principle 5: Inconsistency between severity of infection and clinical symptoms

Transplant recipients depending on their net state of immunosuppression may not adequately demonstrate the typical symptoms and signs that are expected to mirror the severity of infection as seen in immunocompetent individuals. This disparity between severity of infection and the clinical manifestation is mainly due to the decrease in inflammatory response and to the corresponding decrease in pro-inflammatory cytokine production and can have significant clinical consequences in terms of delay

Key principle 6: Emerging and changing patterns of infections posttransplantation

Emergence of newer infections in transplant recipients is not a surprise with the use of newer and more potent immunosuppressive agents. Altering the net state of immunosuppression predisposes to reactivation of endogenous latent bacterial, viral, and fungal infections as seen with BK virus nephropathy after the introduction of CNI drugs. Exogenously acquired infections even at minimal environmental exposure can occur with the use of newer potent drugs. With increasing acceptance of marginal

Key principle 7: Safe living posttransplantation

Patients and their families must receive adequate education regarding increased risk for infections posttransplantation and that educational process should be initiated before transplantation, ideally at the time of evaluation. As the greatest risk for infection is during the first 6 months after transplantation, compliance with clinic visits and antimicrobial prophylaxis needs to be closely monitored. Transplant recipients should be principally educated to avoid environmental exposure to

Key principle 8: Immune monitoring and reconstitution of the immune system during severe infections

The aim of immunosuppressive therapy posttransplantation is to achieve freedom from rejection without complications from overimmunosuppression such as infection and malignancy. The degree to which transplant recipients are immunosuppressed influences their risks for infection, and the net state of immunosuppression refers to all factors that contribute as mentioned in Key Principle 3. Although immunosuppressive drug levels are routinely monitored, they do not always correlate with the degree of

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