NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 1 The Research Institute at Nationwide Children’s Hospital, Center for Clinical and Translational Research, Division of Pediatric Nephrology, 700 Children’s Drive, Columbus, OH 43205, USA (B.B., A.S., J.D.S.). Children’s Foundation Research Institute at Le Bonheur Children’s Hospital, Division of Pediatric Nephrology, 848 Adams Avenue, Memphis, TN 38103, USA (D.S.H.). Correspondence to: B.B. Brian.Becknell2@ nationwidechildrens. org; J.D.S. John.Spencer@ nationwidechildrens. org Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis Brian Becknell, Andrew Schwaderer, David S. Hains and John David Spencer Abstract | Urinary tract infections (UTIs), including pyelonephritis, are among the most common and serious infections encountered in nephrology practice. UTI risk is increased in selected patient populations with renal and urinary tract disorders. As the prevalence of antibiotic-resistant uropathogens increases, novel and alternative treatment options will be needed to reduce UTI-associated morbidity. Discoveries over the past decade demonstrate a fundamental role for the innate immune system in protecting the urothelium from bacterial challenge. Antimicrobial peptides, an integral component of this urothelial innate immune system, demonstrate potent bactericidal activity toward uropathogens and might represent a novel class of UTI therapeutics. The urothelium of the bladder and the renal epithelium secrete antimicrobial peptides into the urinary stream. In the kidney, intercalated cells—a cell-type involved in acid–base homeostasis—have been shown to be an important source of antimicrobial peptides. Intercalated cells have therefore become the focus of new investigations to explore their function during pyelonephritis and their role in maintaining urinary tract sterility. This Review provides an overview of UTI pathogenesis in the upper and lower urinary tract. We describe the role of intercalated cells and the innate immune response in preventing UTI, specifically highlighting the role of antimicrobial peptides in maintaining urinary tract sterility. Becknell, B. et al. Nat. Rev. Nephrol. advance online publication 7 July 2015; doi:10.1038/nrneph.2015.105 Introduction Infection of the lower urinary tract is termed ‘cysti- tis’, whereas an ascending infection that invades the renal parenchyma is termed ‘pyelonephritis’. In 2007, urinary tract infections (UTIs) accounted for over 8.6 million office visits, 600,000 hospitalizations and over US$3.9 billion in hospital costs in the USA alone. 1 In the USA in 2012, acute pyelonephritis accounted for over 200,000 emergency department visits, 64,000 hospital discharges and $378 million in inpatient hos- pital costs. 2 Nearly 50% of women will develop a UTI during their lifetime, and UTI will recur in 25% of these women within 6 months of the initial infection. 3,4 Over half of all recurrent UTIs are caused by the same bacterial strain identified during the initial infection. 5 Escherichia coli is the causative uropathogen in 80% of UTIs; however, other uropathogens—such as Klebsiella spp. or Enterococcus spp.—are more common in immunocompromised patients. 6,7 Certain patient populations—including sexually active and pregnant women, patients with spinal cord disorders, patients who perform bladder catheterization and elderly individuals—are at increased risk of UTI. In nephrology practice, patients with diabetes mellitus, obstructive uropathy, vesicoureteral reflux, structural and cystic kidney disease, and kidney transplant recipients have an increased UTI risk. 8,9 UTIs account for nearly 50% of infectious complications that develop after renal transplantation. 10,11 Acute UTI can lead to the develop- ment of acute kidney injury, bacteraemia, urosepsis and even death. Potential long-term UTI sequelae include hypertension, proteinuria, renal fibrosis and renal insuf- ficiency. In renal transplant recipients, UTIs can impair allograft function and cause allograft loss. 12 No proven treatment options currently exist to prevent UTI sequelae. Thus, new strategies are needed to augment the ability of host defences to prevent UTI and minimize UTI sequelae. Over the past decade, tremendous progress has been made in identifying the host defence mecha- nisms that protect the urothelium from potential patho- gens. Emerging evidence suggests that the innate immune response has a pivotal role in providing the first line of defence against infection and subsequent tissue injury. Additional insight into the mechanisms by which the innate immune system acts in the urinary tract could facili- tate the development of novel therapeutic strategies for acute and recurrent UTI, including severe pyelonephritis. The innate immune system: an overview The innate immune system was once viewed as a ‘stopgap’ host defence mechanism, awaiting support from the humoral and cellular adaptive immune systems. However, the innate immune response is now accepted as a vital, sentinel system with an important role in shielding the host from infection. In contrast to the adaptive immune response, the innate immune system quickly responds to microbial challenge on a timescale that is more rapid than the doubling time of most bacteria. As a result, it provides Competing interests The authors declare no competing interests. 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