AbstractBackgroundIn patients with primary hyperoxaluria (PH), endogenous oxalate overproduction increases urinary oxalate excretion, leading to compromised kidney function and often kidney failure. Highly elevated plasma oxalate (Pox) is associated with systemic oxalate deposition in patients with PH and severe chronic kidney disease (CKD). The relationship between Pox and estimated glomerular filtration rate (eGFR) in patients with preserved kidney function, however, is not well established. Our analysis aimed to investigate a potential correlation between these parameters in PH patients from three randomized, placebo-controlled trials (studies OC3-DB-01, OC3-DB-02, and OC5-DB-01).MethodsBaseline data from patients with a PH diagnosis (type 1, 2, or 3) and eGFR > 40 mL/min/1.73 m2 were analyzed for a correlation between eGFR and Pox using Spearman’s rank and Pearson’s correlation coefficients. Data were analyzed by individual study and additionally were pooled for Studies OC3-DB-02 and OC5-DB-01 in which the same Pox assay was used.ResultsA total of 106 patients were analyzed. A statistically significant inverse Spearman’s correlation between eGFR and Pox was observed across all analyses; correlation coefficients were − 0.44 in study OC3-DB-01, − 0.55 in study OC3-DB-02, − 0.51 in study OC5-DB-01, and − 0.49 in the pooled studies (p < 0.0064).ConclusionsBaseline evaluations showed a moderate and statistically significant inverse correlation between eGFR and Pox in patients with PH already at early stages of CKD (stages 1–3b), demonstrating that a correlation is present before substantial loss in kidney function occurs.Graphical abstract

01 Aug 2018·UrolithiasisQ2 · MEDICINE

A randomised Phase II/III study to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria

Q2 · MEDICINE

Article

Author: Milliner, Dawn ; Groothoff, Jaap ; Hoppe, Bernd

Primary hyperoxaluria (PH) patients overproduce oxalate because of rare genetic errors in glyoxylate metabolism. Recurrent urolithiasis and/or progressive nephrocalcinosis are PH hallmarks and can lead to kidney damage, systemic oxalosis and death. Based on previous studies, we hypothesised that treatment with the oxalate-metabolizing bacterium Oxalobacter formigenes would mediate active elimination of oxalate from the plasma to the intestine of PH patients, thereby reducing urinary oxalate excretion (Uox). The efficacy and safety of O. formigenes (Oxabact™ OC3) were evaluated for 24 weeks in a randomised, placebo-controlled, double-blind study. The primary endpoint was reduction in Uox. Secondary endpoints included change in plasma oxalate (Pox) concentration, frequency of stone events, number of responders, and Uox in several subgroups. Additional post hoc analyses were conducted. Thirty-six patients were randomised; two patients withdrew from placebo treatment. Both OC3 and placebo groups demonstrated a decrease in Uox/urinary creatinine ratio, but the difference was not statistically significant. No differences were observed with respect to change in Pox concentration, stone events, responders' number or safety measures. In patients with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m², Pox increased by 3.25 µmol/L in the placebo group and decreased by -1.7 µmol/L in the OC3 group (p = 0.13). After 24 weeks, eGFR had declined to a greater degree in the placebo than in the OC3 group: -8.00 ± 2.16 versus -2.71 ± 2.50; p = 0.01. OC3 treatment did not reduce urinary oxalate over 24 weeks of treatment compared with placebo in patients with PH. The treatment was well tolerated.

03 Jan 2017·Inorganic ChemistryQ2 · CHEMISTRY

Self-Assembly of Discrete Ru^II₈Molecular Cages and Their in Vitro Anticancer Activity

Q2 · CHEMISTRY

Article

Author: Mukherjee, Partha Sarathi ; Shettar, Abhijith ; Ajibola Adeyemo, Aderonke ; Kondaiah, Paturu ; Bhat, Imtiyaz Ahmad

Four new octanuclear Ru(II) cages (OC-1-OC-4) were synthesized from dinuclear p-cymene ruthenium(II) acceptors [Ru₂(μ-η⁴-C₂O₄)(CH₃OH)₂(η⁶-p-cymene)₂](O₃SCF₃)₂ (A₁), [Ru₂(μ-η⁴-C₆H₂O₄)(CH₃OH)₂(η⁶-p-cymene)₂](O₃SCF₃)₂ (A₂), [Ru₂(dhnq)(H₂O)₂(η⁶-p-cymene)₂](O₃SCF₃)₂ (A₃), and [Ru₂(dhtq)(H₂O)₂(η⁶-p-cymene)₂](O₃SCF₃)₂ (A₄) separately with a tetradentate pyridyl ligand (L₁) in methanol using coordination-driven self-assembly [L₁= N,N,N',N'-tetra(pyridin-4-yl)benzene-1,4-diamine]. The octanuclear cages are fully characterized by various spectroscopic techniques including single-crystal X-ray diffraction analysis of OC-4. The self-assembled cages show strong in vitro anticancer activity against human lung adenocarcinoma A549 and human cervical cancer HeLa cell lines as observed from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Of all the octanuclear cages, OC-3 exhibits remarkable anticancer activity against both cancer cell lines and is more active than that reported for cisplatin. The excellent anticancer activity of OC-3 and OC-4 highlights the importance of the synergistic effects of the spacer component of the dinuclear p-cymene Ru(II) acceptor clips.

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