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 i s 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 i s 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.
A growing number of Veterans suffer from kidney disease. The kidneys get rid of a large number of waste chemicals from our blood. When the function of the kidneys is impaired, these waste chemicals build up in the body. We know little, however, about which chemicals are related to bad outcomes in people with kidney disease. We could treat people better if we identified chemicals that predict which people with kidney disease will develop complete kidney failure and if we identified chemicals that cause symptoms when the kidneys have failed. Our proposed studies will use new methods of chemical analysis incorporating a technique called mass spectrometry to identify such chemicals and will hopefully lead ultimately to improved treatment for our patients.
|Leong, Sheldon C; Sao, Justin N; Taussig, Abigail et al. (2018) Residual Function Effectively Controls Plasma Concentrations of Secreted Solutes in Patients on Twice Weekly Hemodialysis. J Am Soc Nephrol 29:1992-1999|
|Sirich, Tammy L; Meyer, Timothy W (2018) Intensive Hemodialysis Fails to Reduce Plasma Levels of Uremic Solutes. Clin J Am Soc Nephrol 13:361-362|
|Mair, Robert D; Sirich, Tammy L; Plummer, Natalie S et al. (2018) Characteristics of Colon-Derived Uremic Solutes. Clin J Am Soc Nephrol 13:1398-1404|
|Mair, Robert D; Sirich, Tammy L; Meyer, Timothy W (2018) Uremic Toxin Clearance and Cardiovascular Toxicities. Toxins (Basel) 10:|
|Sirich, Tammy L; Fong, Kara; Larive, Brett et al. (2017) Limited reduction in uremic solute concentrations with increased dialysis frequency and time in the Frequent Hemodialysis Network Daily Trial. Kidney Int 91:1186-1192|
|Sirich, Tammy L; Aronov, Pavel A; Fullman, Jonathan et al. (2017) Untargeted mass spectrometry discloses plasma solute levels poorly controlled by hemodialysis. PLoS One 12:e0188315|
|Sirich, Tammy L; Meyer, Timothy W (2017) Manipulating the microbiome. Kidney Int 91:274-276|
|Shafi, Tariq; Sirich, Tammy L; Meyer, Timothy W et al. (2017) Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes. Kidney Int 92:1484-1492|
|Sirich, Tammy L (2017) Obstacles to reducing plasma levels of uremic solutes by hemodialysis. Semin Dial 30:403-408|
|Leong, Sheldon C; Sirich, Tammy L (2016) Indoxyl Sulfate-Review of Toxicity and Therapeutic Strategies. Toxins (Basel) 8:|
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