Infections in Children with Kidney Disease

In this special issue of Journal of Pediatric Infectious Disease, we have compiled eight cutting-edge review articles addressing the prevention, diagnosis, and management of infections in children with a spectrum of kidney disease ranging from neonatal sepsis-associated acute kidney injury (AKI) to the infectious complications of chronic kidney disease including end-stage renal disease (ESRD) on different modalities of renal replacement therapy. The burden of infections in this vulnerable population has been profound despite major improvements in the care of children with acute and chronic kidney disease (CKD) in the past few decades. The survival rate of children with ERSD remains approximately 30 times lower than that of healthy peers[1] [2] with infection being one of the leading causes of death. In addition to the morbidity and mortality associated with infections, infection-related hospitalizations contribute substantially to reduced quality of life, increased school absences, increased health care costs, etc.

The first article focuses on neonatal sepsis-associated AKI—a very real problem today. Of the 6.3 million children who died before age 5 years in 2013, 51.8% (3.257 million) died of infectious causes and 44% (2.761 million) died in the neonatal period.[3] Drs. Nillsen and Kent review and discuss the definition, etiology, and risk factors for neonatal sepsis. They also attempt to describe the complex pathophysiologic processes that predispose neonates with sepsis to AKI, including ischemia, inflammation, and toxic renal injury. This article highlights the importance of neonatal sepsis prevention programs, as neonatal AKI is prevalent after sepsis, and is linked to increased mortality and adverse short- and long-term outcomes.

Extending beyond the neonatal period, severe sepsis carries a hospital mortality rate of 25% in children across the world and accounts for one-third of the pediatric intensive care unit (PICU) deaths.[4] In addition to the mortality risk, sepsis accounts for 50% of AKI in the critically ill.[5] Modern ICU care, including prompt and aggressive antimicrobial use, fluid resuscitation, use of inotropes and vasopressors, mechanical ventilation, and other life support mechanisms, has profoundly impacted the outcomes of sepsis, and yet it remains the leading cause of multiple organ dysfunction in the PICU. Even more worrisome is the multifactorial increase in the prevalence of pediatric sepsis: multidrug-resistant organisms, opportunistic infections, and an increase in pediatric chronic disease and comorbidities being some of the contributing factors. In the second article, Drs. Bridges and Selewski examine the evidence behind extracorporeal therapies for severe sepsis, including continuous renal replacement therapy (CRRT), therapeutic plasma exchange (TPE), and adsorptive therapies. While there is a paucity of pediatric data in these areas, the authors provide evidence supporting the use of CRRT as a first-line modality for sepsis-associated AKI, but the theoretical benefits of convective therapies, TPE, and adsorption therapies require systematic clinical trials before they can be recommended or implemented on a wide scale.

Urinary tract infections (UTIs) are the most common serious pediatric bacterial infection,[6] and recent well-designed studies and multicenter trials have resulted in an evolution in the evaluation and management of pediatric UTIs. In the third article, Drs. Gajjar and Amaral describe the epidemiology and microbiology of UTIs and focus on the controversies and latest literature on the evaluation and management of UTIs in pediatrics. While there remains a lack of consensus regarding imaging recommendations in pediatric febrile UTI, economic and radiation costs must be carefully considered.

The last four articles of this special issue focus on infections in CKD/ESRD and kidney transplant (KTx). In keeping with the phrase “an ounce of prevention is worth a pound of cure” before delving into the infectious ramifications of CKD, ESRD on dialysis, and KTx, Drs. Khalid and Nailescu discuss in detail infection prevention with a focus on vaccination strategies. Their thorough review addresses infection prevention in children with chronic glomerular disorders, such as nephrotic syndrome and complement disorders, including atypical hemolytic uremic syndrome; C3 glomerulopathy and dense deposit disease; CKD and ESRD; and pre- and post-KTx.

While the challenges faced by children with CKD and ESRD are profound, they are further heightened in developing countries, where in addition to the inherent risk of infection from CKD itself, unsafe water, suboptimal sanitation, and hygiene services cause unacceptably high morbidity and mortality from common childhood infections including diarrhea and pneumonia. Dr. Pais admirably argues for the need of dedicated nephrology care, regulated dialysis facilities, and infection control with improved attention to overall health of the general population in developing countries. She highlights the need for basic health programs and improved vaccination strategies, things taken for granted in the developed world.

There are currently almost 10,000 prevalent pediatric patients receiving maintenance dialysis in the United States alone. Children on dialysis are at increased risk for infection compared with their healthy peers likely due to a multitude of factors, including vaccine hyporesponsiveness, immunosuppressive therapy, uremia, immune dysfunction inherent to ESRD patients, the dialysis catheter, and the method of the dialysis procedure itself. The sixth article by Drs. Nicoara, Somers, and Chand is a deft and succinct review of the risk factors, etiology, therapy, and outcomes of infections associated with peritoneal dialysis (PD). A commonly used dialysis modality particularly in small children, PD is highly efficacious and easily done at home providing the benefit of less disruption to school attendance and better quality of life. This article covers peritonitis, PD catheter exit site, and tunnel infections, and prompts readers to be vigilant for signs and symptoms of infection with prompt diagnosis and therapy to prevent long-term complications and preserve the PD catheter and the peritoneal membrane integrity.

The infectious complications of hemodialysis are similarly covered by Dr. Munshi in the seventh article. The most common initial dialysis modality in pediatrics, hemodialysis in children is most often via a central venous catheter, and consequently infectious complications account for considerable morbidity and hospitalization. This review evaluates the risk factors, strategies for prevention, and approaches to therapy of infections in hemodialysis patients. Dr. Munshi stresses that the onus of infection preventive strategies and screening protocols is on the hemodialysis programs and that adherence to the Centers for Disease Control and Prevention (CDC) guidelines and center protocols is critical at least until the multicenter data from the Standardized Care to improve Outcomes in Pediatric ESRD (SCOPE) are available.

Successful renal transplantation is the optimal treatment for chronic kidney failure, and modern immunosuppression has profoundly reduced rejection risk. However, infection is now the dominant cause of pediatric hospitalizations and death after transplant,[7] and many infectious agents are oncogenic, dramatically increasing the lifetime risk of cancer for pediatric transplant recipients. In the final article in this special issue, Dixon and Twombley discuss four organisms that can be problematic post-KTx: Epstein-Barr virus; known for its potential to cause a premalignant posttransplant lymphoproliferative disorder; the cytomegalovirus, an ongoing problem despite excellent antiviral drugs such as valganciclovir; BK virus, a papova virus, which can cause BK nephropathy leading to graft loss[8] [9]; and Pneumocystis jirovecii, a rare but potentially fatal infectious complication of immunocompromised pediatric KTx recipients.

This special issue of Infections in Children with Kidney Disease will provide readers a balanced and comprehensive review of the burden, etiology, risk factors, and therapeutic and preventive strategies for infections in children with kidney disease.

• References

• 1 Harambat J, van Stralen KJ, Kim JJ, Tizard EJ. Epidemiology of chronic kidney disease in children. Pediatr Nephrol 2012; 27 (03) 363-373
• 2 McDonald SP, Craig JC. ; Australian and New Zealand Paediatric Nephrology Association. Long-term survival of children with end-stage renal disease. N Engl J Med 2004; 350 (26) 2654-2662
• 3 Liu L, Oza S, Hogan D. , et al. Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet 2015; 385 9966 430-440
• 4 Proulx F, Joyal JS, Mariscalco MM, Leteurtre S, Leclerc F, Lacroix J. The pediatric multiple organ dysfunction syndrome. Pediatr Crit Care Med 2009; 10 (01) 12-22
• 5 Ruth A, McCracken CE, Fortenberry JD, Hall M, Simon HK, Hebbar KB. Pediatric severe sepsis: current trends and outcomes from the Pediatric Health Information Systems database. Pediatr Crit Care Med 2014; 15 (09) 828-838
• 6 Montini G, Tullus K, Hewitt I. Febrile urinary tract infections in children. N Engl J Med 2011; 365 (03) 239-250
• 7 Kirk AD, Mannon RB, Swanson SJ, Hale DA. Strategies for minimizing immunosuppression in kidney transplantation. Transpl Int 2005; 18 (01) 2-14
• 8 Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet 1971; 1 7712 1253-1257
• 9 Drake KA, Najera L, Reed RC, Verghese PS. Unusual presentations of BK virus infections in pediatric renal transplant recipients. Pediatr Transplant 2013; 17 (01) E9-E15