New Solutes to Assess Kidney Disease

描述（由申请人提供）： 肾脏从血浆中清除大量有机溶质。然而，关于这些溶质与肾脏疾病患者健康结果之间的关系，人们知之甚少。现在的护理几乎完全通过仅测量两种溶质（肌酐和尿素）来指导，已知这两种溶质是临床事件的不完美预测因子。拟议的研究将采用新的质谱方法来识别与重要临床结局相关的其他溶质。这些“代谢组学”方法允许同时测量单个样品中的许多溶质。目前的建议将这些方法应用于两个主要的临床问题。第一个目的是确定肾小管分泌受损预测慢性肾脏疾病进展的溶质。在关注肾小球功能时，肾病学家忽略了肾小管分泌受损预测慢性肾病（CKD）进展的可能性。该候选人最近采用高分辨率非靶向质谱法来鉴定由正常肾脏非常有效地分泌的溶质。拟定的研究将使用类似的方法询问CKD患者前瞻性研究中适当储存的样本。非靶向质谱法将鉴定分泌受损可能与大鼠CKD进展相关的候选溶质。后续研究将确定目标溶质的化学特性。然后将采用同位素稀释串联质谱法进行更多定量测定，以确认特定溶质与更大人群中疾病进展的关系。 结果将检验以下假设：肾小管分泌受损可独立于已建立的标志物预测肾脏疾病进展的风险。第二个目的是确定可能导致尿毒症症状的溶质。当肾脏衰竭时，我们对哪些滞留溶质导致疾病知之甚少。拟定的研究将使用非靶向质谱法来询问维持血液透析患者的血浆样本。非靶向质谱法将识别可能与突出尿毒症症状相关的候选溶质。后续研究将确定目标溶质的化学特性。然后将采用同位素稀释串联质谱法进行更多的定量测定，以确认更大人群中特定溶质与症状的关系。结果将检验假设，即最先进的质谱法可以识别与尿毒症症状相关的保留溶质。这两个目标都旨在产生新的化学知识，这些知识可以促进未来临床试验的设计，并可能导致新的治疗方法。

DESCRIPTION (provided by applicant): The kidneys remove numerous organic solutes from the plasma. Remarkably little is known, however, about the relation between these solutes and health outcomes in patients with kidney disease. Care is now guided almost exclusively by measurement of only two solutes, creatinine and urea, which are known to be imperfect predictors of clinical events. The proposed study will employ new mass spectrometric methods to identify additional solutes associated with important clinical outcomes. These "metabolomic" methods allow for the simultaneous measurement of numerous solutes in individual samples. The current proposal will apply these methods to two major clinical problems. The first aim is to identify solutes for which impaired tubular secretion predicts the progression of chronic kidney disease. In focusing on glomerular function, nephrologists have neglected the possibility that impaired tubular secretion predicts the progression of chronic kidney disease (CKD). The candidate has recently employed high resolution untargeted mass spectrometry to identify solutes which are very efficiently secreted by the normal kidneys. The proposed study will use similar methods to interrogate appropriately stored samples from prospective studies of patients with CKD. Untargeted mass spectrometry will identify candidate solutes for which impaired secretion is potentially associated with the rat of progression of CKD. Follow-up studies will establish the chemical identity of solutes of interest. More quantitative assays using tandem mass spectrometry with isotopic dilution will then be employed to confirm the relation of specific solutes to progression in a larger population. Results will test the hypothesis that impaired tubular secretion predicts the risk of kidney disease progression independent of established markers. The second aim is to identify solutes which may cause uremic symptoms. We know remarkably little about which retained solutes cause illness when the kidneys fail. The proposed studies will use untargeted mass spectrometry to interrogate plasma samples from patients maintained on hemodialysis. Untargeted mass spectrometry will identify candidate solutes potentially associated with prominent uremic symptoms. Follow-up studies will establish the chemical identity of solutes of interest. More quantitative assays using tandem mass spectrometry with isotopic dilution will then be employed to confirm the relation of specific solutes to symptoms in a larger population. Results will test the hypothesis that state of the art mass spectrometry can identify retained solutes associated with uremic symptoms. Both aims are designed to yield new chemical knowledge which could facilitate the design of future clinical trials and potentially lead to new methods of treatment.