Search

Persistent mild to moderate hyperoxaluria (PMMH) is a common side effect of bariatric surgery. However, PMMH's role in the progression to calcium oxalate (CaOx) urolithiasis and its potential effects on non-renal tissues are unknown. To address these points, a trigger + maintenance (T + Mt) model of PMMH was developed in rats (Experiment 1). The trigger was an i.p. injection of PBS (T PBS) or 288 μmol sodium oxalate (T 288). Maintenance (Mt) was given via minipumps dispensing PBS or 7.5–30 μmol potassium oxalate/day for 28 days. Urinary oxalate ranged from 7.7 ± 0.8 μmol/day for T PBS + Mt PBS to 18.2 ± 1.5 μmol/day for T 288 + Mt 30 ( p ≤ 0.0005). All rats receiving T 288 developed CaOx nephrocalcinosis, and many developed ‘stones’. This was also true for Mt doses that did not elevate urinary oxalate above that of T PBS + Mt PBS ( p > 0.1) and for rats that did not have a detectable surge in urinary oxalate post T 288. When T PBS was administered, CaOx nephrocalcinosis did not develop regardless of the Mt dose even if urinary oxalate was elevated compared to T PBS + Mt PBS ( p ≤ 0.0005). One of the risks associated with PMMH is oxalate accumulation within tissues. Hence, in a second set of experiments (Experiment 2) different doses of oxalate (Mt 0.05, Mt 15, Mt 30) labeled with 14C-oxalate ( 14C-Ox) were administered by minipump for 13 days. Tissues were harvested and 14C-Ox accumulation assessed by scintillation counting. 14C-Ox accumulated in a dose dependent manner ( p ≤ 0.004) in bone, kidney, muscle, liver, heart, kidney, lungs, spleen, and testis. All these tissues exhibited 14C-Ox concentrations higher ( p ≤ 0.05) than the plasma. Extrapolation of our results to patients suggests that PMMH patients should take extra care to avoid dietary-induced spikes in oxalate excretion to help prevent CaOx nephrocalcinosis or stone development. Monitoring for oxalate accumulation within tissues susceptible to damage by oxalate or CaOx crystals may also be required. [ABSTRACT FROM AUTHOR]

Extracellular inorganic pyrophosphate (PPi) is a potent suppressor of physiological calcification in bone and pathological calcification in blood vessels. Ectonucleotide pyrophosphatase/phosphodiesterases (eNPP5) generate PP via the hydrolysis of ATP released into extracellular compartments by poorly understood mechanisms. Here we report that cultured vascular smooth muscle cells (VSMC) from rat aorta generate extracellular PPi via an autocrine mechanism that involves ATP release tightly coupled to eNPP activity. The nucleotide analog β-γ-methylene ATP (MeATP or AMPPCP) was used to selectively suppress ATP metabolism by eNPPs but not the CD39-type ecto-ATPases. In the absence of MeATP, VSMC generated extracellular PP to accumulate ⩾600 nM within 2 h while steadily maintaining extracellular ATP at 1 nM. Conversely, the presence of MeATP completely suppressed PPi accumulation while increasing ATP accumulation. Probenecid, which inhibits PPi efflux dependent on ANK, a putative PPi transporter or transport regulator, reduced extracellular PPi accumulation by approximately twofold. This indicates that autocrine ATP release coupled to eNPP activity comprises ⩾0% of the extracellular PP-generating capacity of VSMC. The accumulation of extracellular PPi and ATP was markedly attenuated by reduced temperature but was insensitive to brefeldin A, which suppresses constitutive exocytosis of Golgi-derived secretory vesicles. The magnitude of extracellular PP accumulation in VSMC cultures increased with time postplating, suggesting that ATP release coupled to PPi generation is upregulated as cultured VSMC undergo contact-inhibition of proliferation or deposit extracellular matrix. [ABSTRACT FROM AUTHOR]