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Metabolomics in monitoring kidney transplantsDavid S. Wishart The success of any given kidney transplant is closely tied to the ability to monitor patients and responsively change their medications. Transplant monitoring is still, however, dependent on relatively old technologies: serum creatininelevels, urine output, blood pressure, blood glucose and ß 2006 Lippincott Williams & Wilkins histopathology of biopsy samples. These older technologies do not offer sufficient specificity, sensitivity, oraccuracy to allow appropriate and timely interventions.
Using the tools of genomics, proteomics and metabolomics new biomarkers are being found that may greatly improve The first successful kidney transplant was performed transplant monitoring and significantly enhance graft more than 50 years ago In the intervening period, survival. This review describes the basic principles of kidney transplantation has become the most successful metabolomics and summarizes a number of recent and widespread organ transplant operation performed developments in the use of metabolite biomarkers and today. Kidney transplants now account for more than metabolomics to monitor kidney transplants.
60% of the 25 000 organ transplants performed annually in North America. This life-saving, life-transforming Changes in the concentration profiles of a number of small surgery would not be possible without carefully con- molecule metabolites found in either blood or urine can be trolled immunosuppression. Prior to the development used to localize organ damage, identify organs at risk of of modern immunosuppressive techniques, 1-year graft rejection, assess organs suffering from ischemia– survival was less than 65% Thanks to the develop- repurfusion injury or identify organs that have been ment of calcineurin inhibitors and other modern immu- nosuppressive therapies, 1-year postengraftment survival now approaches 90% Long-term organ survival, how- The application of metabolomics to kidney transplant ever, is not yet optimal. About 25% of all kidney trans- monitoring is still very much in its infancy. Nevertheless, plants fail within 5 years after transplantation while there are a number of easily measured metabolites in both 10-year graft survival rates range from 33% for deceased urine and serum that can provide reliable indications of donor kidneys to 67% for living donor grafts organ function, organ injury, and immunosuppressive drugtoxicity. As the field matures, metabolomics may eventually Transplants may fail for any number of reasons including lead to the development of rapid, inexpensive and preoperative organ stress, surgical complications, post- noninvasive approaches to assist clinicians in monitoring operative infection, acute rejection, or immunosuppres- sive nephrotoxicity. Organ loss is not the only concern.
Transplant patients also face increased risks for devel- oping diabetes, atherosclerosis, hyperlipidemia, hyper- kidney transplant, metabolites, metabolomics, renal tension, chronic viral infections (hepatitis B virus, cytomegalovirus or BK virus), bone disease and lym-phoma Because of the ever-present risk of post- Curr Opin Nephrol Hypertens 15:637–642. ß 2006 Lippincott Williams & Wilkins.
engraftment failure and other health complications,kidney transplant patients must be monitored closely, aDepartments of Biological Sciences and Computing Science, University of Albertaand bNational Research Council, National Institute for Nanotechnology (NINT), requiring regular checks on renal function, cardiac func- tion, signs of infection and immunosuppressive drug Correspondence to David Wishart, 2-21 Athabasca Hall, University of Alberta, Edmonton, AB, Canada T6G 2E8Tel: +1 780 492 0383; fax: +1 780 492 1071; e-mail: The monitoring of transplants and transplant patients, Current Opinion in Nephrology and Hypertension 2006, 15:637–642 however, is still dependent on somewhat older technol-ogies: serum creatinine levels, total urine output, bodytemperature, blood pressure or blood glucose. In somecases, these simple clinical assays do not offer sufficientspecificity, sensitivity, or accuracy to allow appropriate Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
and timely interventions. As a result, costly follow-up became possible with the advent of recent technological biopsies and time-consuming histopathological measure- breakthroughs in small molecule separation and identi- ments are typically required to make definitive diag- fication. These include the development of capillary noses. Recent studies suggest that even these ‘gold- electrophoresis and ultra-high pressure liquid chromatog- standard’ histology assays are not without their problems raphy (UPLC) systems for rapid compound separation, Given these limitations, more and more transplant the invention of robust mass spectrometry instruments specialists are looking to the emerging fields of genomics, for precise mass determination, the development of high- proteomics and metabolomics to improve the current resolution, high throughput nuclear magnetic resonance (NMR) spectrometers and the creation of new softwaretools to rapidly process spectral or chromatographic The hope is that these high-throughput ‘omic’ tech- patterns With these hardware and software inno- niques could help identify combinations of biomarkers vations it is now possible to identify and quantify not just that might be used to inexpensively and noninvasively one or two small molecules at a time, but literally dozens identify transplantation problems far earlier and far more of small molecule metabolites in as little as a few minutes robustly than is currently possible. Proteomic methods have already identified several urinary protein bio- metabolomics is what distinguishes it from more markers that seem to robustly identify acute rejection and other renal disorders Similar collections of transcript biomarkers have also been identified fromkidney biopsies using microarray experiments As In clinical chemistry, most metabolites are typically we shall see later, however, small molecule metabolites identified and quantified using colorimetric chemical may well prove to be the most useful biomarkers for assays. In metabolomics, a large number of metabolites monitoring kidney function and detecting adverse renal are measured using non-chemical, non-colorimetric events. This is because the kidney is fundamentally a methods such as gas chromatography –mass spectro- metabolic organ designed to concentrate or filter small metry, tandem mass spectrometry or NMR spectroscopy.
molecule metabolites and small molecule toxins. There- Interestingly, in some versions of metabolomic analysis, fore one should expect changes in metabolite levels in the compounds are not identified; only their spectral blood or urine to be both more detectable and more patterns and intensities are recorded In other reflective of kidney function than subtle changes to versions of metabolomic analysis, all (or most) of the the kidney’s proteome or transcriptome compounds are identified and quantified The former approach is based strongly on computer- In this review we will look at how the measurement of aided pattern recognition and sophisticated statistical metabolites or metabolic profiles can be used to monitor techniques. The latter approach relies on spectral kidney function. Specifically we will cover three areas in curve-fitting and prior chemical or spectral knowledge.
which metabolite measurements or metabolomic studies Both methods have their advantages and disadvantages, are having an impact in renal transplantation. These although there is a strong preference for absolute include the application of metabolomics towards asses- compound identification and quantification.
sing ischemia–reperfusion injury; assessing immunosup-pressive drug toxicity and monitoring transplant organ Just as genes and proteins are normally associated with function and localizing organ damage. Before addressing specific pathways and processes, so too are metabolites.
these specific applications in kidney transplantation, As might be expected, most of the small molecule however, it is perhaps worthwhile to briefly discuss the metabolites measured by metabolomic methods are tied to generic metabolic processes (glycolysis, gluconogen-esis, lipid metabolism) found in all living cells. Changes in the relative concentrations of certain ‘universal’ meta- bolites such as glucose, citrate, lactate, 2-oxoglutarate and measurement of large numbers of small molecule others reflect changes in cell viability (apoptosis), levels (<1500 Da) metabolites. Just as genes are part of the of oxygenation (anoxia, ischemia, oxidative stress), local genome and proteins are part of the proteome, meta- pH, general homeostasis and so on These molecules bolites are part of the metabolome. The metabolome obviously can be quite informative of cell function or is the collection of all small molecule metabolites cell stress, and therefore organ function. Other kinds (endogenous or exogenous) that can be found in a cell, of metabolites are specifically associated with tissue organ or organism. Metabolomics is a relatively new term, remodeling, muscle atrophy and myofibrillar breakdown having been coined in 2000 Metabolomics is also (methyl-histidine, creatine, tuarine, glycine). Changes in known as metabonomics or metabolic profiling .
the levels of these metabolites can provide important Just like genomics and proteomics, metabolomics only information about the extent of tissue repair or tissue Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Metabolomics in kidney transplants Wishart damage Some compounds, such as trimethyla- close similarity between rat and human metabolism, it mine-N-oxide (TMAO), are actually used as buffers to is likely that the findings in these rat models will translate stabilize serum proteins from the effects of accumulated waste products . In other words, each metabolite hasits own story to tell. The challenge for both the physician The lone human study on ischemia –repurfusion injury and the scientist is to figure out what that story is.
used metabolic profiling to identify the presence ofsignificantly elevated serum levels of hypoxanthine and inosine (hypoxanthine nucleoside) following kidney reperfusion Hypoxanthine and inosine are both Kidney transplantation is particularly traumatic to a well known markers of ischemia and oxidative damage.
healthy donor organ as it requires the removal of the Both molecules are typically formed as breakdown pro- organ from the host blood supply for a lengthy period of ducts of ATP. Hypoxanthine can be converted to time (ischemia time). Obviously, the shorter the ischemia xanthine and then to uric acid via an enzyme called time the better the chance the organ has of recovering xanthine oxidoreductase. As an oxidase, this enzyme uses and functioning. Longer periods of ischemia are known to molecular oxygen as electron acceptor and generates a seriously damage most kidneys In addition, tissues superoxide along with other reactive oxygen products, can also be damaged by the reoxygenation or reperfusion which upon reperfusion and re-oxygenation can lead to process. Reperfusion injury is a term used for the tissue further oxidative tissue damage. While this study did not damage caused when the blood supply returns to the correlate the levels of ischemia–repurfusion injury or transplanted organ after an extended period of ischemia.
graft function with hypoxanthine levels, it does reaffirm The absence of blood oxygenation creates a condition that better markers for ischemia –repurfusion injury do in which restored circulation results in inflammation exist. Collectively, these studies illustrate that metabo- lomic methods could significantly improve the monitor- than restoration of normal function. This damage is ing of ischemia –repurfusion injury and further enhance caused by white blood cells, inflammatory proteins and our understanding of the effects of ischemia and free radicals flowing back into the tissue during the reperfusion after kidney transplantation.
The identification of ischemia –repurfusion injury in newly transplanted kidneys is particularly challenging.
Kidney transplants would not be possible without immu- Current methods rely on relatively simple and nonspe- nosuppressive therapies. Immunosuppression for kidney cific measures such as serum creatinine, urine output and transplant recipients, however, can also lead to nephro- biopsies As a result there has been a growing toxicity as well as elevated risks for cardiovascular interest in the development of more reliable biomarkers disease (CVD), diabetes and cancer. The detection and less invasive procedures, including metabolomic and monitoring of these adverse drug effects are particu- methods. To date most metabolomic studies on ischemia– larly challenging as relatively few tests exist for measur- ing immunosuppressive drug or drug metabolite levels and no single test exists for detecting the wide range of known adverse drug effects. Metabolomics may offer an studies found that the extent of ischemia –repurfusion answer to these problems. A key advantage of metabo- injury was correlated with elevated levels of citrate, lomics over other ‘omic’ approaches is the fact that dimetheylamine, lactate and acetate in the urine. It metabolomics is ideally suited for monitoring drugs was also noted that ischemia–repurfusion injury was and drug metabolites as well as for tracking the drug- highly correlated with increased levels of allantoin induced changes to organ function and organ metabolism.
(50–100 times normal) and TMAO in the blood. Allan- This application is particularly important for the immu- toin, which is an oxidative product of uric acid, is a nosuppressive drugs cyclosporine, sirolimus and tacroli- common marker of oxidative cell stress. On the other mus. These potent drugs exhibit large inter-individual hand, TMAO is a homeostatic ‘rescue’ compound that variability in their metabolism and a narrow therapeutic allows blood proteins to handle increased concentrations of urea and guanidine (both strong protein denaturants)that arise during renal failure or renal stress Calcineurin inhibitors are metabolized by two cyto- Additionally TMAO is known to be a marker of renal chrome P450 variants known as CYP3A4 and CYP3A5.
medullar injury. Surprisingly, it was determined that Polymorphisms in these enzymes leading to ‘ultrafast’ serum creatinine levels, which have long been used as or ‘ultraslow’ metabolizers may have significant con- an injury marker, did not correlate with the level of sequences for organ function and patient health ischemia –reperfusion damage Because of the To help address this issue, metabolomic techniques (high Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
pressure liquid chromatography –mass spectrometry) Metabolomics to assess organ function and have recently been developed to rapidly track serum concentrations of cyclosporine A (CsA) and five of its As has been remarked earlier, posttransplant monitoring known metabolites among transplant recipients of organ function is particularly important for identifying Interestingly the concentration of one particular CsA signs of renal dysfunction, for localizing organ damage or metabolite, known as AM19, was found to correlate for detecting the early stages of acute rejection. Close strongly with several inflammatory and atherosclerotic monitoring can allow preemptive or corrective action to markers. These data suggest that adverse effects may be be implemented before the organ is irreparably damaged.
predicted and mitigated by using metabolomics to track Outside of serum creatinine measurements to assess gross certain CsA metabolite concentrations. Similar high- organ function and protocol biopsies to help localize organ damage, however, relatively few alternative tests methods have also been used to develop effective blood are being used. Given the demonstrated potential of assays to monitor the concentrations of the immunosup- metabolite measurements, this is somewhat surprising.
pressant mycophenolic acid and its metabolites Indeed, over the past 20 years more than 30 metabolomicpapers have been published describing a plethora of In addition to these drug-oriented metabolic profiling urinary and serum biomarkers associated with posttrans- studies, several NMR and mass spectrometry-based plantation function, renal dysfunction, acute rejection, metabolomic studies recently appeared that describe subclinical rejection and localized organ damage. One the consequences of CsA on endogenous metabolites feature common to almost all of these studies is the These effects, which were assayed using rat substantial (three to four-fold) increase seen in both urine models, include elevated levels of urinary glucose, and serum concentrations of TMAO As noted acetate, trimethylamine and succinate along with before, this metabolite is a homeostatic rescue compound reduced levels of urinary TMAO, kynurenate, xanthur- that helps stabilize serum proteins from the effects of enate, citrate and riboflavin . A more recent study accumulated waste products. In addition to reports of focusing on serum instead of urinary metabolites elevated levels of TMAO, other organic amines (tri- found that both CsA and sirolimus led to elevated levels methylamine, dimethylamine) and amino acids (glycine, of glucose, hydroxybutyrate, creatine, creatinine, TMAO alanine) have also been found. Metabolomic studies of and cholesterol along with reduced concentrations of transplanted, dysfunctional or rejected kidneys have also glutathione in the blood. These results are consistent been used to detect the presence of elevated (two to five- with many of the calcineurin inhibitor complications seen fold) serum levels of nephrotoxins such as hippuric acid in humans including diabetes (elevated glucose in urine and uric acid Kidney dysfunction is also associ- and blood, elevated hydroxybutyrate), heightened risk of ated with elevated serum levels of nitric oxide synthase CVD (reduced riboflavin, elevated cholesterol), medullar inhibitors such as phenylacetic acid and dimethy- damage (elevated serum TMAO and creatinine levels), larginine which lead to significantly reduced nitric increased incidence of kidney stones (low levels of oxide production Reduced nitric oxide levels are citrate), proximal tubule damage (reduced kynurenate often correlated with hypertension and cardiovascular and xanthurenate) and general oxidative stress (high complications, both of which tend to further diminish levels of acetate and succinate, reduced glutathione).
kidney function. Damaged kidneys also appear to rapidly Metabolomic studies in humans have shown similar elevate serum and urinary levels of lactate, acetate, CsA toxicity profiles including reduced citrate and succinate, citrate and urea, which are generally con- increased oxalate levels increased cholesterol or sidered to be markers of Kreb’s cycle (i.e. metabolic) LDL levels increased malondialdehyde (a marker distress, increased anaerobic metabolism and tubular for oxidative stress) and glucose intolerance In acidosis The identification of these previously addition, human metabolic profiling studies focused on unidentified metabolic imbalances is leading to thera- CsA and tacrolimus toxicity have shown increased levels peutic and dietary interventions that appear to have some of serum uric acid (a well known nephrotoxin) as well as increased levels of homocysteine and otherCVD risk markers Noninvasive (i.e. biopsy-free) approaches to localizeorgan damage are another area where metabolomic Overall, these results illustrate the potential of using approaches may eventually find some clinical utility.
metabolomics as a ‘one-stop’ shop for assessing immu- A growing body of research is accumulating which shows nosuppressive drug toxicity. Metabolomics appears to be that it is possible to correlate localized kidney damage flexible enough to allow for the noninvasive tracking of with distinct metabolite patterns For example, using drug and drug metabolite levels (i.e. exogenous metab- olites) as well as the noninvasive tracking of endogenous researchers have found that damage to the proximal straight tubules (via D-serine) is typically associated with Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Metabolomics in kidney transplants Wishart increased levels of lactate along with elevated levels of Murray JE, Barnes BA, Atkinson JC. Fifth report of the Human KidneyTransplant Registry. Transplantation 1967; 5:752–755.
the amino acids tryptophan, phenylalanine, tyrosine, Cecka JM. The UNOS Scientific Renal Transplant Registry – 2000. Clin tyrosine and valine Straight tubule injury is also manifested by reduced levels of methylsuccinic, sebacic Cecka JM. The OPTN/UNOS renal transplant registry. Clin Transpl 2004; 1–16.
and xanthurenic acid. Meanwhile damage to the proximal Oberholzer J, Testa G, Sankary H, et al. Kidney transplantation at the convoluted tubules (via gentamicin) is generally associ- University of Illinois at Chicago from 1988–2004. Clin Transpl 2004;143–149.
ated with elevated levels of urinary glucose and reduced Djamali A, Premasathian N, Pirsch JD. Outcomes in kidney transplantation.
levels of TMAO, xanthurenic acid and kynurenic acid On the other hand it has been noted that renal Hariharan S. BK virus nephritis after renal transplantation. Kidney Int 2006; papillary and medullar injury (via bromoethaneamide) is This nice review describes the emerging importance of the BK (polyoma) virus in characterized by increased urinary concentrations of glu- taric acid, creatine and adipic acid along with reduced Veronese FV, Manfro RC, Roman FR, et al. Reproducibility of the Banff classification in subclinical kidney transplant rejection. Clin Transplant levels of citrate, succinate, oxoglutarate and TMAO In contrast, renal cortical damage (via mercuric chloride) The authors use a multipathologist assessment to highlight the problems asso-ciated with using the Banff classification protocol in identifying and classifying is associated with increased urinary glucose, alanine, transplant rejection events by histopathology.
valine, lactate, hippurate and decreased citrate, succinate Schaub S, Rush D, Wilkins J, et al. Proteomic-based detection of urine and oxoglutarate While it may be some time before proteins associated with acute renal allograft rejection. J Am Soc Nephrol2004; 15:219–227.
these animal model results can be translated to humans in 10 O’Riordan E, Goligorsky MS. Emerging studies of the urinary proteome: the the transplant clinic, the possibility of using simple end of the beginning? Curr Opin Nephrol Hypertens 2005; 14:579–585.
metabolic profiles to noninvasively characterize the foci This is a useful review about the emerging importance and untapped potential ofurinary proteomics in monitoring renal function.
of organ damage is obviously quite appealing.
11 Eikmans M, Roos-van Groningen MC, Sijpkens YW, et al. Expression of surfactant protein-C, S100A8, S100A9, and B cell markers in renal allografts: investigation of the prognostic value. J Am Soc Nephrol 2005; 16:3771–3786.
The application of metabolomics to kidney transplant This is a nice example of how transcriptomics and microarrays can be used to monitoring is still very much in its infancy. It is now quite identify specific biomarkers for predicting transplant outcomes.
12 Wishart DS. Metabolomics: the principles and applications to transplantation.
apparent that there are a number of metabolites that Am J Transplant 2005; 5:2814–2820.
can be easily measured in both urine and serum and can This is the first review published on the topic of metabolomics and organ provide reliable indications of organ function, organ transplantation. It provides a good historical overview of metabolic profiling beingapplied to monitor a wide range of solid organ transplants.
injury, and immunosuppressive drug toxicity. Indeed 13 Drysdale R, Bayraktaroglu L. Current awareness. Yeast 2000; 17:159–166.
the American Society of Nephrology has recently 14 Nicholson JK, Lindon JC, Holmes E. ‘Metabonomics’: understanding the endorsed the development of core metabolomics facili- metabolic responses of living systems to pathophysiological stimuli via multi-variate statistical analysis of biological NMR spectroscopic data. Xenobiotica ties to facilitate the centralized processing of biologic materials As the field advances, it is likely that 15 Thompson JA, Markey SP. Quantitative metabolic profiling of urinary organic more metabolite markers or more specific metabolic acids by gas chromatography –mass spectrometry: comparison of isolationmethods. Anal Chem 1975; 47:1313–1321.
profiles will be discovered and clinically validated, allow- 16 Dunn WB, Bailey NJ, Johnson HE. Measuring the metabolome: current ing even more precise diagnostic determinations. While analytical technologies. Analyst 2005; 130:606–625.
metabolomics clearly offers a number of exciting pro- This is a superb summary of the technologies and general methodologicalapproaches being used in metabolomics. It is well written and very comprehensive.
spects, one must always remember that metabolites are 17 Lindon JC, Holmes E, Bollard ME, et al. Metabonomics technologies and their only a small part of the biological picture. Understanding applications in physiological monitoring, drug safety assessment and disease organ rejection, detecting certain kinds of organ injury or diagnosis. Biomarkers 2004; 9:1–31.
predicting the outcome of an organ transplant will 18 Smith IC, Baert RL. Medical diagnosis by high resolution NMR of human specimens. IUBMB Life 2003; 55:273–277.
always require the input from many disciplines and many 19 Wishart DS, Querengesser LMM, Lefebvre BA, et al. Magnetic resonance diagnostics: a new technology for high-throughput clinical diagnostics. ClinChem 2001; 47:1918–1921.
Bell JD, Lee JA, Lee HA, et al. Nuclear magnetic resonance studies of bloodplasma and urine from subjects with chronic renal failure: identification of The author wishes to thank Genome Alberta (a division of Genome trimethylamine-N-oxide. Biochim Biophys Acta 1991; 1096:101 –107.
Canada), the National Institute for Nanotechnology (NINT) and the 21 Serkova N, Fuller TF, Klawitter J, et al. H-NMR-based metabolic signatures of Canada Foundation for Innovation (CFI) for financial support.
mild and severe ischemia/reperfusion injury in rat kidney transplants. KidneyInt 2005; 67:1142–1151.
This well designed and informative study identifies, quantifies and explains the origins of many endogenous metabolites arising from ischemia–repurfusion injury.
Papers of particular interest, published within the annual period of review, have It is an excellent example of a modern metabolomic study applied to kidney 22 Fuller TF, Serkova N, Niemann CU, Freise CE. Influence of donor pretreatment with N-acetylcysteine on ischemia/reperfusion injury in rat kidney grafts. J Urol Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 665–666).
23 Hauet T, Baumert H, Gibelin H, et al. Noninvasive monitoring of citrate, Murray JE, Merrill JP, Harrison JH. Renal homotransplantation in identical acetate, lactate and renal medullary osmolyte excretion in urine as biomarkers twins. Surg Forum 1955; 6:432–437.
of exposure to ischemic reperfusion injury. Cryobiology 2000; 41:280–291.
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24 Domanski L, Safranow K, Dolegowska B, et al. Hypoxanthine as a graft 37 Armstrong KA, Johnson DW, Campbell SB, et al. Does uric acid have a ischemia marker stimulates catalase activity in the renal vein during reperfu- pathogenetic role in graft dysfunction and hypertension in renal transplant sion in humans. Transplant Proc 2006; 38:35–38.
recipients? Transplantation 2005; 80:1565 –1571.
This solid paper describes the identification and tracking of serum hypoxanthine This well controlled and statistically robust study reported the generally high and inosine as markers for ischemic damage.
incidence of elevated uric acid levels in renal transplant patients.
25 Al Banchaabouchi M, Marescau B, D’Hooge R, et al. Biochemical and 38 Wong W, Tolkoff-Rubin N, Delmonico FL, et al. Analysis of the cardiovascular histopathological changes in nephrectomized mice. Metabolism 1998; risk profile in stable kidney transplant recipients after 50% cyclosporine reduction. Clin Transplant 2004; 18:341–348.
26 Thervet E, Legendre C, Beaune P, Anglicheau D. Cytochrome P450 3A 39 Foxall PJ, Mellotte GJ, Bending MR, et al. NMR spectroscopy as a novel polymorphisms and immunosuppressive drugs. Pharmacogenomics 2005; approach to the monitoring of renal transplant function. Kidney Int 1993; This paper reviews the status of the pharmacogenomics and pharmacokineticsassociated with CYP3A variants in calcineurin inhibitor metabolism.
40 Le Moyec L, Pruna A, Eugene M, et al. Proton nuclear magnetic resonance 27 Vollenbroeker B, Koch JH, Fobker M, et al. Determination of cyclosporine and spectroscopy of urine and plasma in renal transplantation follow-up. Nephron its metabolites in blood via HPLC-MS and correlation to clinically important parameters. Transplant Proc 2005; 37:1741 –1744.
41 Knoflach A, Binswanger U. Serum hippuric acid concentration in renal The authors describe an mass spectrometry-based method that allows detection allograft rejection, ureter obstruction and tubular necrosis. Transpl Int and quantification of cyclosporine and five of its metabolites. They also associate outcome with the presence of a particular CsA metabolite.
42 Jankowski J, van der Giet M, Jankowski V, et al. Increased plasma phenylacetic 28 Annesley TM, Clayton LT. Quantification of mycophenolic acid and glucur- acid in patients with end-stage renal failure inhibits iNOS expression. J Clin onide metabolite in human serum by HPLC-tandem mass spectrometry. Clin This paper outlines an mass spectrometry-based method for the detection and 43 Zoccali C, Kielstein JT. Asymmetric dimethylarginine: a new player in the quantification of mycophenolate mofetil and its metabolites that is more accurate pathogenesis of renal disease? Curr Opin Nephrol Hypertens 2006; and sensitive than current immunoassays.
29 Lenz EM, Bright J, Knight R, et al. Cyclosporin A-induced changes in 44 Dedeoglu IO, Feld LG. Decreased urinary excretion of nitric oxide in acute endogenous metabolites in rat urine: a metabonomic investigation using high rejection episodes in pediatric renal allograft recipients. Transplantation field 1H NMR spectroscopy, HPLC-TOF/MS and chemometrics. J Pharm 45 Yatzidis H. Oral supplement of six selective amino acids arrest pro- 30 Serkova NJ, Christians U. Biomarkers for toxidynamic monitoring of immuno- gression renal failure in uremic patients. Int Urol Nephrol 2004; 36: suppressants: NMR-based quantitative metabonomics of the blood. Ther This is another excellent example that illustrates the power of using NMR to identify 46 Albrecht EW, van Goor H, Smit-van Oosten A, Stegeman CA. Long-term and quantify changes in endogenous metabolites associated with calcineurin dietary L-arginine supplementation attenuates proteinuria and focal glomer- ulosclerosis in experimental chronic renal transplant failure. Nitric Oxide2003; 8:53–58.
31 Stapenhorst L, Sassen R, Beck B, et al. Hypocitraturia as a risk factor for nephrocalcinosis after kidney transplantation. Pediatr Nephrol 2005; 47 Holmes E, Nicholls AW, Lindon JC, et al. Chemometric models for toxicity classification based on NMR spectra of biofluids. Chem Res Toxicol 2000; The authors describe and quantify the reduction in citrate and the increase in oxalate that appears to arise from CsA toxicity.
48 Williams RE, Major H, Lock EA, et al. D-Serine-induced nephrotoxicity: a 32 Tse KC, Lam MF, Yip PS, et al. A long-term study on hyperlipidemia in stable HPLC-TOF/MS-based metabonomics approach. Toxicology 2005; 207: renal transplant recipients. Clin Transplant 2004; 18:274–280.
This is an interesting example of an mass spectrometry-based metabolomic study 33 Moreno JM, Ruiz MC, Ruiz N, et al. Modulation factors of oxidative status in to identify the metabolic consequences of focal kidney lesions brought on by the stable renal transplantation. Transplant Proc 2005; 37:1428 –1430.
This describes and quantifies the reduction in malondialdehyde levels and elevatedglutathione peroxidase activity as a result of immunosuppressive therapy.
49 Lenz EM, Bright J, Knight R, et al. Metabonomics with 1H-NMR spectroscopy 34 Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant and liquid chromatography–mass spectrometry applied to the investigation of recipients: effect of calcineurin inhibitor withdrawal and conversion to siro- metabolic changes caused by gentamicin-induced nephrotoxicity in the rat.
limus. J Am Soc Nephrol 2005; 16:3128–3135.
This highlights the problems of immunosuppression-induced diabetes and the fact This describes a well integrated (NMR and mass spectrometry) metabolomic study that neither CsA, tacrolimus or sirolimus appear to offer any improvement.
aimed at identifying the metabolic consequences of localized kidney damagebrought on by genatamicin, a nephrotoxin.
35 Kanbay M, Akcay A, Huddam B, et al. Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney transplant recipients. Transplant 50 Lenz EM, Bright J, Knight R, et al. A metabonomic investigation of the biochemical effects of mercuric chloride in the rat using 1H NMR and The authors measured the incidence of elevated levels of uric acid found in renal HPLC-TOF/MS: time dependent changes in the urinary profile of endo- transplant recipients and noted that both CsA and tacrolimus lead to comparable genous metabolites as a result of nephrotoxicity. Analyst 2004; 129:535 – 36 Perico N, Codreanu I, Caruso M, Remuzzi G. Hyperuricemia in kidney 51 American Society of Nephrology. American Society of Nephrology Renal transplantation. Contrib Nephrol 2005; 147:124–131.
Research Report. J Am Soc Nephrol 2005; 16:1886–1903.
This nice review explains the importance of uric acid in contributing to transplant This report outlines the strategic research goals and research tools that will facilitate renal studies for the next decade.
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Society of Nuclear Medicine Procedure Guideline for C-14 Urea Breath Test version 3.0, approved June 23, 2001 Authors: Helena R. Balon, MD (William Beaumont Hospital, Royal Oak, MI); Eileen Roff, RN, MSA, (William BeaumontHospital, Royal Oak, MI); John E. Freitas, MD (St. Joseph Mercy Hospital, Ann Arbor, MI); Vanessa Gates, MS (WilliamBeaumont Hospital, Royal Oak, MI); and Howard J. Dworkin,

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