Response to letter regarding article, ‘proton pump inhibitors in IPF: beyond mere suppression of gastric acidity’

We thank the authors, Dr Hill and Dr Sayer, for their feedback in response to our article published inQJM: An International Journal of Medicine.1 In principle, we agree with the authors and the recent population-based observational studies2 that chronic use of proton pump inhibitors (PPIs) may adversely affect renal physiology including development and/or progression of chronic kidney disease (CKD). Our earlier work3 applying molecular, cell biological and preclinical models found that PPIs directly inhibit the activity of dimethylarginine dimethylaminohydrolase (DDAH); an enzyme that is expressed in different segments of the kidney including proximal tubule, thick ascending limb of the loop of Henle, macula densa, distal convoluted tubule and collecting ducts. Inhibition of renal DDAH enzymatic activity by PPIs is expected to deregulate the endogenous concentration of its substrate asymmetrical dimethylarginine (ADMA); competitive inhibitor of nitric oxide (NO) synthase (NOS). Thus, PPIs could disrupt the DDAH/ADMA/NO homeostasis in the renal system by elevating ADMA levels and suppressing DDAH and NO. Several preclinical and clinical studies indicate that dysfunction of NO, an important molecule in the dilation of afferent and efferent arterioles, is associated with systemic and glomerular hypertension, glomerular ischemia, proteinuria, tubulointerstitial injury, renal fibrosis, progression of CKD and end-stage renal disease (ESRD).4 The studies also report that urinary or ...
Source: QJM - Category: Internal Medicine Source Type: research