Bill & Melinda Gates Foundation.

No abstract

Bill & Melinda Gates Foundation.

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR Ն40 ml/min per 1.73 m 2 . In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46 Ϯ 81 ml; P ϭ 0.047) than on conventional therapy (70 Ϯ 72 ml; P ϭ 0.002), but we did not detect a difference between the two treatments (P ϭ 0.45). Cyst volume was stable on sirolimus and increased by 55 Ϯ 75 ml (P ϭ 0.013) on conventional therapy, whereas parenchymal volume increased by 26 Ϯ 30 ml (P ϭ 0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Background/Aims: Nephrotoxicity is the major limitation to cisplatin therapy for solid tumors. We aimed at evaluating whether early increases in serum/urine levels of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of tubular damage and regeneration, predict cisplatin-induced acute kidney injury (AKI). Methods: We compared changes in serum creatinine and serum/urine NGAL levels (ELISA assay) at 1 and 4 h and 1, 2, 3, 7 and 15 days after cisplatin infusion (70–80 mg/m²) versus baseline in 12 consecutive cancer patients (cases) with AKI (>25% serum creatinine increase vs. baseline) and 12 consecutive controls without AKI. Results: Baseline characteristics and posttreatment serum NGAL levels were similar in both groups. Urinary NGAL levels increased significantly more in cases than in controls at 1, 2, 3 and 15 days after cisplatin. The NGAL increase preceded AKI by 4.5 days and the NGAL increase at day 2 after cisplatin independently predicted AKI (p < 0.05). Six cases with residual kidney dysfunction at 15 days showed a trend to earlier and higher increase in urinary NGAL levels compared to cases with renal function recovery. Conclusion: An early increase in urinary NGAL excretion may help in identifying patients at risk of cisplatin-induced AKI who might benefit from innovative treatments to prevent cisplatin nephrotoxicity.