PATHOPHYSIOLOGY OF IDIOPATHIC URIC ACID NEPHROLITHIASIS

尿酸(UA)肾结石占美国肾结石的5-8%。尿酸结石的主要原因是尿液pH值偏高，尿酸滴定为不溶形式。虽然众所周知，低尿酸是病因，但低酸碱症的病因仍不明确。本P01明确了本病的6个病理生理特征：1.尿路结石患者常有代谢综合征的临床征象。2.糖尿病结石患者尿酸肾结石的发生率为40%，而普通结石人群的UA肾结石发生率约为6%。3.尿液酸碱度低是由于肾脏不能排出主要成分。 尿液中的缓冲氨使更多的H+处于游离态。4.尿酸结石患者的酸性尿液pH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，用噻唑烷二酮类药物逆转外周胰岛素抵抗可使尿液pH值恢复正常。6.鼠肾上皮细胞胰岛素缺乏和胰岛素抵抗均与肾上皮细胞转运蛋白Na~+/H~+交换器NHE3的表达和功能降低有关，NHE3有助于排氨。我们假设：1.胰岛素抵抗是尿酸肾结石的主要危险因素。 2.“肾脏胰岛素抵抗”表现为低铵排泄和酸性尿液pH。3.胰岛素可通过多种机制导致肾脏酸化异常，其中一种机制是NHE3功能受损，导致氨排出障碍。目的1将对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(葡萄糖处置速率)和肾脏胰岛素敏感性(尿酸分析)进行量化，并检查外周和肾脏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将使这些人承受任一重量 减少，吡格列酮，或两者兼而有之，以改善他们的胰岛素抵抗。目的3利用胰岛素抵抗的啮齿动物模型(ZDF大鼠)，研究肾脏酸化缺陷的病理生理机制(以及NHE3介导的铵转运)。目的4重点阐述胰岛素调节NHE3的分子机制。我们将UA肾结石从一种经验性综合征转变为一种合理的病因机制。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.