PATHOPHYSIOLOGY OF IDIOPATHIC URIC ACID NEPHROLITHIASIS

在美国，尿酸（UA）肾结石占肾结石的5-8%。大多数尿酸结石是由于酸性尿pH滴定尿酸至其不溶性形式。虽然低尿pH值是众所周知的病因，低pH值的病因学仍然是模糊的。本P01明确了本病的6个病理生理特征：1。尿酸结石患者的临床表现常常让人联想到代谢综合征。2.糖尿病结石患者UA肾结石的发病率为40%，而一般结石患者的发病率约为6%。3.低尿pH值是由于肾脏不能排泄主要的 尿缓冲氨使更多的H+处于游离状态。4.尿酸结石患者的酸性尿pH值与外周胰岛素抵抗程度呈定量正相关。5.在初步的一组患者中，噻唑烷二酮类逆转外周胰岛素抵抗使尿液pH值正常化。啮齿类动物中肾上皮细胞中的胰岛素缺乏和胰岛素抵抗均与上皮转运蛋白Na+/H+交换器NHE 3的表达和功能降低相关，NHE 3有助于铵的排泄。我们假设1。胰岛素抵抗是UA肾结石的主要危险因素。 2.“肾胰岛素抵抗”表现为低铵排泄和酸性尿pH。胰岛素可通过多种机制引起肾脏酸化异常;其中之一是NHE 3功能受损，导致铵排泄受损。目的1将量化具有广泛外周胰岛素敏感性的受试者的外周胰岛素敏感性（葡萄糖处置率）和肾胰岛素敏感性（尿酸化测定），并检查外周与肾胰岛素抵抗程度的定量相关性。然而，相关性并不能证明因果关系。目标2将使这些人受到以下两种重量的限制： 损失，吡格列酮，或两者，以改善他们的胰岛素抵抗。目的3将使用胰岛素抵抗的啮齿动物模型（ZDF大鼠）并检查肾酸化缺陷的病理生理学（除了NHE 3介导的铵转运）。目的4研究胰岛素调节NHE 3的分子机制。我们已经将UA肾结石从经验性综合征转变为我们有合理病因机制的综合征。这项研究将为肾脏胰岛素抵抗的新概念奠定基础，并为UA肾结石的诊断和治疗选择开辟新的途径。

Uric acid (UA) nephrolithiasis constitutes 5-8% of kidney stones in the United States. The majority of UA stones are due to acidic urinary pH titrating UA to its insoluble form. Although low urinary pH is well known to be causative, the etiology of the low pH remains lusive. This P01 has defined 6 pathophysiologic features of this disease: 1. UA stone-formers often have a clinical picture reminiscent of the metabolic syndrome. 2. The incidence of UA nephrolithiasis among diabetic stone-formers is 40% compared to about 6% incidence in the general stone-former population. 3. The low urinary pH is due to inability of the kidney to excrete the major urinary buffer ammonia leaving more H+ in its free state. 4. The acidic urinary pH in UA stone-formers is quantitatively and positively correlated with the degree of peripheral insulin resistance. 5. In a preliminary group of patients, reversal of peripheral insulin resistance by thiazolidinediones normalizes the urine pH. 6. Insulin deficiency in renal epithelial cells and insulin resistance in rodents are both associated with reduced expression and function of the epithelial transporter Na+/H+ exchanger NHE3 which contributes to excretion of ammonium. We hypothesize that 1. Insulin resistance constitute a major risk factor for UA nephrolithiasis. 2. "Renal insulin resistance" manifests as low ammonium excretion and acidic urinary pH. 3. Insulin can cause the renal acidification abnormality by multiple mechanisms; one of which is impaired NHE3 function leading to impaired ammonium excretion. Aim 1 will quantify peripheral insulin sensitivity (glucose disposal rate) and renal insulin sensitivity (urinary acidification assays) in subjects with a wide range of peripheral insulin sensitivity, and examine for quantitative correlation of the degree of peripheral vs. renal insulin resistance. However, correlation does not prove causality. Aim 2 will subject these individuals to either weight loss, piioglitazone, or both to improve their insulin resistance. Aim 3 will use the rodent model of insulin resistance (ZDF rat) and examine the pathophysiology of renal acidification defect (in addition to NHE3-mediated ammonium transport). Aim 4 will focus on the molecular mechanism of regulation of NHE3 by insulin. We have taken UA nephrolithiasis from an empirical syndrome to one where we have plausible etiologic mechanisms. This study will lay the foundation for novel concepts of renal insulin resistance and open new avenues for diagnostic and therapeutic options for UA nephrolithiasis.