Omeprazole-induced acute interstitial nephritis: a possible Th1-Th17-mediated injury?

BACKGROUND: Omeprazole is an important cause of drug-induced acute interstitial nephritis (AIN). How omeprazole induces injury is unknown. METHODS AND RESULTS: Detailed clinical assessment of 25 biopsy-proven cases of omeprazole-induced AIN showed that all patients presented with impaired renal function, sterile pyuria with varying amounts of proteinuria but no eosinophiluria and no systemic symptoms to suggest a vasculitis. Histological analyses were characteristic of an acute tubulitis with an inflammatory cellular infiltrate. Using modified Banff scheme criteria, mild tubulitis (t1) was present in 56% of cases, a moderate tubulitis (t2) in 24% of cases, and a severe tubulitis in 20% of cases. Most (78%) of cases had mononuclear cell infiltrates, no significant eosinophilic infiltrates were found, and glomeruli were not involved. Immunostaining for CD4, CD8, IL-17A, IL-17F, Foxp3 and T-bet (T cell subsets), CD20 and CD163 defined the cellular infiltrates. The predominant inflammatory cells were CD4+ lymphocytic aggregates (77% of cases), combined with co-staining of CD4 IL and 17A/F in 44-48% of all cases, suggesting a Th17-mediated inflammatory process. T-bet+ cell infiltrates were present to a lesser degree, suggesting additional Th1 involvement. How omeprazole induces this inflammatory response is unclear, but may include direct effects by IL-17 expressing CD4+ cells on renal tubular cells. CONCLUSION: This large biopsy series of omeprazole-induced AIN demonstrates the features of acute tubulitis, with significant interstitial infiltrates consistent with immunopathological Th17 and Th1 processes.

Dietary salt loading impairs arterial vascular reactivity.

BACKGROUND: Studies of sodium have shown improvements in vascular function and blood pressure (BP). The effect of chronic sodium loading from a low-sodium diet to a Western diet on vascular function and BP has been less well studied. OBJECTIVE: The objective was to examine the effects of dietary salt intake on vascular function and BP. DESIGN: Thirty-five hypertensive volunteers met the inclusion criteria. After a 2-wk run-in with a low-sodium diet (60 mmol/d), the participants maintained their diets and were randomly assigned to receive sequentially 1 of 3 interventions for 4 wk, with a 2-wk washout between interventions: sodium-free tomato juice (A), tomato juice containing 90 mmol Na (B), and tomato juice containing 140 mmol Na (C). The outcomes were changes in pulse wave velocity (PWV), systolic BP (SBP), and diastolic BP (DBP). RESULTS: The difference in PWV between interventions B and A was 0.39 m/s (95% CI: 0.18, 0.60 m/s; P < or = 0.001) and between C and A was 0.35 m/s (95% CI: 0.13, 0.57 m/s; P < or = 0.01). Differences in SBP and DBP between interventions B and A were 4.4 mm Hg (95% CI: 1.2, 7.8 mm Hg; P < or = 0.01) and 2.4 mm Hg (95% CI: 0.8, 4.1 mm Hg; P < or = 0.001), respectively, and between interventions C and A were 5.6 mm Hg (95% CI: 2.7, 8.4 mm Hg; P < or = 0.01) and 3.3 mm Hg (95% CI: 1.5, 5.0 mm Hg; P < or = 0.001), respectively. Changes in PWV correlated with changes in SBP (r = 0.52) and DBP (r = 0.58). CONCLUSIONS: Dietary salt loading produced significant increases in PWV and BP in hypertensive volunteers. Correlations between BP and PWV suggest that salt loading may have a BP-independent effect on vascular wall function. This further supports the importance of dietary sodium restriction in the management of hypertension. This trial was registered with the Australian and New Zealand Clinical Trials Registry as ACTRN12609000161224.