Ayurvedic medicine and NADPH oxidase: a possible approach to the prevention of ESRD in hyperoxaluria

Abstract

Saeed Khan’s longstanding commitment to investigating the pathogenesis of renal stones adds to our knowledge ever more with new evidence to support the hypothesis that exposure of the renal tubular cells to high oxalate and calcium oxalate (CaOx) crystals triggers an oxidative stress cascade that has a pivotal role in crystal retention in the kidney. In this Nephrology Dialysis Transplantation issue, Zuo et al. [1] clearly demonstrates in a model of hyperoxaluria that inhibiting reactive oxygen species (ROS) synthesis reduces tubular injury and prevents crystal retention in thekidney.Inaway,theyhavecompleted 30yearsofstudies which began after the serendipitous observation reported by Baggio et al. [2] that idiopathic CaOx stone formers have tubular damage, as shown by their increased urinary excretion of proximal tubule enzymes. Unfortunately, there is no valid model of human idiopathic calcium oxalate nephrolithiasis (ICN), although there are many models of hyperoxaluria. Mild hyperoxaluria, i.e. an oxalate excretion of up to 60 mg/24 h, is frequently observed in ICN patients [3], but the urinary excretion of oxalate is much higher in the rare secondary hyperoxalurias and the even rarer primary hyperoxalurias, generally exceeding 100 mg/24 h. The experimental models used by many groups (including Khan’s laboratory) to investigate CaOx stone pathogenesis reflect, in our opinion, the conditions of primary and secondary hyperoxalurias rather than the more common, mild hyperoxaluria. In these experimental models, crystals are actually observed intraluminally in the upper nephron and downstream, and they are deposited mainly in the interstitium. While neither of these findings have ever been described in ICN patients, they are typically seen in the nephrocalcinosis of primary and secondary hyperoxaluria. For the above reasons, we believe that the results of the investigations performed by Khan et al. in models of severe hyperoxaluria pertain to a different scenario from ICN. The findings reported by Baggio et al. most likely derive from a different pathogenic sequence. We have advanced the hypothesis that ICN has a two-hits pathogenesis: the first hit is a tubular injuring factor which facilitates CaOx crystal formation in the presence of a mild hyperoxaluria (second hit), possibly by delivering cell debris [4]. This corresponds with many findings in ICN and is consistent with the Randall’s plaque theory of lithogenesis—probably the most rational explanation for stone formation in the kidney: according to this theory, stones grow in the renal pelvis on Randall’s plaques, not in the tubular lumen. Of course, the possibility of the tubular injury observed in ICN patients (the first hit) being caused by an oxidative stress (which is easy to envisage in these patients) cannot be ruled out. For instance, there is a known association between metabolic syndrome and hypertension with renal stones, and both conditions are associated with oxidative stress. In this sense, inhibiting ROS synthesis, as in the experi