HISTOPATHOLOGIC DETERMINANTS OF HUMAN NEPHROLITHIASIS

人类肾结石的组织病理学决定因素

• 批准号: 7490030
• 负责人: ANDREW P EVAN
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490030
• 关键词: Acids; Amaze; Apatites; Bariatrics; Binding; Bowman' s space; Calcium; Calcium Oxalate; Calculi; Cells; Characteristics; Clinical; Condition; Crystal Formation; Cystine; Cystinuria; Deposition; Disease; Duct (organ) structure; Family suidae; Functional disorder; Funding; Grant; Growth; Henle' s loop; Histopathology; Human; Hydroxyapatites; Hyperparathyroidism; Ileostomy; Injury; Intestinal Bypasses; Kidney; Kidney Calculi; Kidney Papilla; Limb structure; Liquid substance; Lithotripsy; Metabolic; Minerals; Modeling; Nephrolithiasis; Obesity; Operative Surgical Procedures; Osteoblasts; Papillary; Pathogenesis; Patients; Pattern; Phenotype; Process; Proteins; Prothrombin; Reverse Transcriptase Polymerase Chain Reaction; Shock; Site; Spectroscopy, Fourier Transform Infrared; Techniques; Testing; Tetracycline; Tetracyclines; Tissues; Transcript; Tubular formation; Uric Acid; Urine; Water; alpha-Fetoproteins; bariatric surgery; base; bikunin; brushite; calcium phosphate; cell injury; insight; interstitial; interstitial cell; migration; osteopontin; particle; prothrombin fragment 1; response; urinary

Our histopathologic studies performed during the previous grant period have characterized the histopathological and mineral composition in three groups of stone formers: common idiopathic calcium oxalate stone formers, patients with stones due to intestinal bypass surgery for obesity and brushite stone formers (as well as non-stone formers) to test the hypothesis that Randall's plaque, calcium phosphate deposits in kidneys of patients with calcium renal stones, arise in unique anatomical regions of the kidney, their formation conditioned by specific stone-forming pathophysiologies. We were amazed at the finding, in that, each group of stone formers had a different and unique histopathologic pattern of crystal desposition while all intraparenchymal and interstitial sites of crystalline material were hydroxyapatite, yet another surprise. Because we were so highly successful in the last funding period in identifying a clear set of surgical/ morphological/metabolic characteristics in these three different groups of human stone formers (CaOx, intestinal bypass for obesity and brushite) and will extend these analyses to new groups of stone formers: apatite (including RTAs) stone formers, primary hyperparathyroidism with kidney stones, ileostomy with kidney stones, cystine stone formers, uric acid stones, bariatric patients with stones and CaOx stone formers with high urine pH (> pH 6.3) using histopathology,mu CT, and mu FTIR. In addition, we will seek to test a new set of hypotheses concerning the mechanisms of stone formation. First, we will test the hypothesis that the progression of HA accumulation occurs along a specific segment of the loops of Henle, the thin descending limb. Second, the mechanism of crystal particle formation and coalescence in the common CaOx patients will be determined by quantitative TEM and tetracycline studies. Third, test the hypothesis that there are candidate proteins that either promote or inhibit crystal nucleation and growth within the papillary interstitium or tubular lumens. This will be done using TEM immunohistochemical analysis to define the interaction of osteopontin, prothrombin fragment 1,fetuin-A and bikunin on interstitial and the plaque-stone interface. Fourth, we will use RT-PCR techniques to detect transcripts for the presence of osteoblast-like activity. Lastly, we will examine the idea that a loss of fluid pH control in the inner medullary collecting ducts due to SWL injury may result in an alkalization of the bulk urine and, therefore, give insights into the mechanisms of stone formation in brushite stone disease.

我们的组织病理学研究在上一个资助期进行的特点是， 三组结石形成者的组织病理学和矿物组成：常见的特发性草酸钙结石形成者、因肥胖而接受肠旁路手术的结石患者和透钙磷石结石形成者（以及非结石形成者）来检验以下假设：兰德尔斑块，即钙肾结石患者肾脏中的磷酸钙沉积物，出现在肾脏的独特解剖区域中，它们的形成受特定的结石形成病理生理学的制约。我们对这一发现感到惊讶，因为每组结石形成者具有不同且独特的晶体沉积组织病理学模式，而所有实质内和间质部位的晶体物质均为羟基磷灰石，这是另一个惊喜。因为我们在上一个资助期非常成功地确定了一套清晰的外科/ 这三组不同的人类结石形成者的形态/代谢特征（CaOx，肥胖症和透钙磷石的肠旁路），并将这些分析扩展到新的结石形成者组：磷灰石（包括RTA）结石形成者、原发性甲状旁腺功能亢进伴肾结石、回肠造口术伴肾结石、胱氨酸结石形成者、尿酸结石，使用组织病理学、mu CT和mu FTIR对患有结石的肥胖患者和具有高尿液pH（> pH 6.3）的CaOx结石形成者进行了研究。此外，我们将试图测试一套新的假设有关的机制，石头的形成。首先，我们将测试假设， HA积累的进展发生在沿着Henle袢的特定段，即细的下行支。第二，晶体颗粒的形成和合并在常见的CaOx患者的机制将通过定量TEM和四环素的研究。第三，检验是否存在促进或抑制乳头状小管或肾小管内晶体成核和生长的候选蛋白质这一假设。这将使用TEM免疫组织化学分析来确定骨桥蛋白、凝血酶原片段1、胎球蛋白-A和bikunin在间质和斑块-结石界面上的相互作用。第四，我们将使用RT-PCR技术来检测转录本是否存在成骨细胞样活性。最后，我们将研究的想法，液体pH值控制的损失，由于SWL损伤可能会导致大量尿液的碱化，因此，给透钙磷石结石病的结石形成机制的见解。