Clinical and Functional Characterization of URAT1 Variants

Idiopathic renal hypouricaemia is an inherited form of hypouricaemia, associated with abnormal renal handling of uric acid. There is excessive urinary wasting of uric acid resulting in hypouricaemia. Patients may be asymptomatic, but the persistent urinary abnormalities may manifest as renal stone disease, and hypouricaemia may manifest as exercise induced acute kidney injury. Here we have identified Macedonian and British patients with hypouricaemia, who presented with a variety of renal symptoms and signs including renal stone disease, hematuria, pyelonephritis and nephrocalcinosis. We have identified heterozygous missense mutations in SLC22A12 encoding the urate transporter protein URAT1 and correlate these genetic findings with functional characterization. Urate handling was determined using uptake experiments in HEK293 cells. This data highlights the importance of the URAT1 renal urate transporter in determining serum urate concentrations and the clinical phenotypes, including nephrolithiasis, that should prompt the clinician to suspect an inherited form of renal hypouricaemia

Effects of irbesartan on serum uric acid levels in patients with hypertension and diabetes

Makiko Nakamura,1 Nobuo Sasai,2 Ichiro Hisatome,3 Kimiyoshi Ichida11Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; 2Sasai Clinic, Kanagawa, Japan; 3Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Tottori, JapanBackground: Hyperuricemia has been proposed to be a risk factor for cardiovascular disease and chronic kidney disease. Since diabetes is often complicated by hypertension and hyperuricemia, efficient therapeutic strategy against these two complications is very important in diabetic treatment. It has been reported that the antihypertensive drug, irbesartan, inhibits the renal uric acid reabsorptive transporters, URAT1 and GLUT9; this result suggests that irbesartan decreases serum uric acid level (SUA).Subjects and methods: A retrospective study of 107 patients with hypertension and diabetes was performed to analyze the effects of irbesartan on blood pressure, estimated glomerular filtration rate (eGFR), and SUA. The follow-up period was 6–12 months. Seventy percent of the patients were diagnosed with diabetic nephropathy stage II–IV. We excluded patients treated with drugs that influenced SUA. The multiple logistic regression analysis was introduced to identify the relative factors for SUA decline. The time-dependent SUA changes were examined in a mixed-linear model.Results: Irbesartan reduced blood pressure significantly after 1, 6, and 12 months’ treatment. No subject showed significant change in eGFR from baseline level throughout the period. The multiple logistic regression analysis revealed that SUA baseline significantly influenced SUA decline after 6–12 months. In patients whose SUA baseline was ≥5.9 mg/dL, the SUA was significantly decreased from 6.6±0.16 mg/dL to 6.2±0.16 mg/dL (P=0.010), after 12 months’ irbesartan treatment. In the SUA baseline <5.9 mg/dL group, the SUA did not show significant change over the monitoring period.Conclusion: Our results demonstrate that irbesartan reduces the risk of hyperuricemia. No decline in renal function was observed after the initiation of irbesartan treatment. The present report determines the criteria of SUA baseline for introducing an antihyperuricemic effect using irbesartan. Its antihypertensive effect coupled with SUA decline would be effective for the treatment of hypertension complicated by hyperuricemia.Keywords: angiotensin-receptor blocker, diabetes, hypertension, hyperuricemia, serum uric aci

[3]Ferrocenophanes with a tetramethyldisiloxane bridge: synthesis and molecular structure

Siemeling U, Krallmann R, Jutzi P, Neumann B, Stammler H-G. [3]Ferrocenophanes with a tetramethyldisiloxane bridge: synthesis and molecular structure. Monatshefte für Chemie. 1994;125(5):579-586.6,6,8,8-Tetramethyl-7-oxa-6,8-disila[3]-ferrocenophan 2 entsteht aus dem Di(alkoxysilyl)ferrocen (H4C5SiMe2OR)2Fe (R=CH2CH2OCH2CH2OCH2CH2OMe) durch Hydrolyse und anschließende intramolekulare Disiloxan-Bildung. 2,2',3,3',4,4',5,5',6,6,8,8-Dodecamethyl-7-oxa-6,8-disila[3]ferrocenophan 3 wurde durch Luftoxidation von 2,2',3,3',4,4',5,5',6,6,7,7-Dodecamethyl-6,7-disila[2]ferrocenophan erhalten. Die Kristallstrukturen beider Verbindungen wurden durch Einkristall-Röntgenstrukturanalyse bestimmt (2:a=8.5330(10), b=15.610(3), c=18.774(5)Å, [alpha]=70.68(2), [beta]=77.94(2), [gamma]=75.150(10)°, V=2259.8(8)Å3, Z=6, Raumgruppe P1, R=0.045, Rw =0.044; 3:a=12.388(3), b=9.924(3), c=19.136(10)Å, [beta]=105.11(3)°, V=2271.2(15)Å3, Z=4, Raumgruppe P21/c, R=0.076, Rw =0.060). Wegen der Flexibilität der Disiloxan-Brücke sind 2 und 3 ungespannte Moleküle

Update in uric acid, hypertension, and cardiovascular diseases

A direct relationship between serum uric acid levels and hypertension, cardiovascular, renal and metabolic diseases has been reported in many basic and epidemiological studies. Among these, high blood pression is one of the most common features associated with hyperuricemia. In this regard, several small-scale interventional studies have demonstrated a significant reduction in blood pressure in hypertensive or prehypertensive patients on uric acid-lowering drugs. These observation or intervention studies have led to affirm that there is a causal relationship between uric acid and hypertension. While the clinical association between uric acid and high blood pressure is notable, no clear conclusion has yet been reached as to whether lowering uric acid is beneficial to prevent cardiovascular and renal metabolic diseases. Recently, several prospective randomized controlled intervention trials using allopurinol and other uric acid-lowering drugs have been reported, and the results from these trials were almost negative, suggesting that the correlation between hyperuricemia and cardiovascular disease has no causality. However, it is important to note that in some of these recent studies there were high dropout rates and an important fraction of participants were not hyperuricemic. Therefore, we should carry caution in interpreting the results of these studies. This review article presents the results of recent clinical trials using uric acid-lowering drugs, focusing on hypertension and cardiovascular and renal metabolic diseases, and discusses the future of uric acid therapy