Clinical data from many parts of the world document a specific and unusual phenotype in infants and children with different types of reflux or obstructive uropathies. The phenotype includes repetitive and severe urinary infections, a change in the urine composition including alkalosis and reduced ammonia trapping, and progressive interstitial infiltrates in the kidney. UTI-Pyelonephritis is generally the presenting complaint, but alkaline urine has been found in 50% of patients and kidney damage is thought to be inevitable without medical or surgical intervention. While the literature is consistent, a cellular explanation is lacking that unifies these clinical phenomena. It is known that organs that access the outside environment contain specialized cells that resist bacterial invasion, including Paneth cells in the gastrointestinal tract, intercalated cells in the frog skin, and clear cells in the epididymis. These cells not only secrete antimicrobial peptides but additionally can acidify or alkalinize the media as part of their bacteriostatic activities. The kidney contains rows of cells called ?-intercalated cells (?-IC). These cells secrete H+, which acidified the urine in range pH 4.5 - 6.3. Acidified urine was known (Shohl&Janney J Urology.1917) to inhibit the growth of E. coli and other urinary organisms, but acid-base balance rather than a dedicated role in antimicrobial defense has been assigned to ?-ICs. Remarkably, these cells are targets of urinary bacteria and LPS, which directly bind the cells and activates expression of cytokines in a TLR4 dependent fashion. The ?-IC then secrete a number of antimicrobial proteins including the iron-siderophore scavenger called NGAL, and they acidity the urine and may sequester iron. In this light, ?-ICs are sensors of UTI, and effectors of antimicrobial responses. In fact, the deletion of ?-cells or the knockout of NGAL prolongs the UTI and reduces urinary acidification demonstrating a phenotype highly reminiscent of reflux and obstruction. To test the link between reflux-obstruction and the ?-cell, we have invented tools to see reflux and obstruction, UTI, and kidney damage in real time, and we have identified an essential transcriptional regulator of IC cells. We propose that while the flow disturbance is essential to locate the infection from bladder to kidney, the innate immune responses of IC cells determine the severity of the infection. In sum, we propose that the ?-IC is a novel member of the innate immune family of cells which is dysregulated by reflux-obstruction and secondly that these syndromes result in two hits flow disturbances and immune dysregulation at the level of the kidney s collecting ducts.
Our work describes the cellular mechanism that the kidney utilizes to determine the composition of the urine. We propose that diseases that change the flow of urine interrupt these mechanisms so that a syndrome which includes infection and kidney damage arises. The work is not only applicable to congenital abnormalities but additionally may explain a similar clinical presentation in acquired diseases of the urinary tract.
|Bao, Guan-Hu; Barasch, Jonathan; Xu, Jie et al. (2015) Purification and Structural Characterization of "Simple Catechol", the NGAL-Siderocalin Siderophore in Human Urine. RSC Adv 5:28527-28535|
|Verbitsky, Miguel; Sanna-Cherchi, Simone; Fasel, David A et al. (2015) Genomic imbalances in pediatric patients with chronic kidney disease. J Clin Invest 125:2171-8|