Urinary biomarkers for the early detection of acute and chronic allograft dysfunction.
1. Introduction
Kidney may undertake normal function immediately after transplantation or even several or over a dozen days delay. Absence of normal renal transplant function may lead to acute kidney injury (AKI), nephrotic syndrome (NS) and chronic kidney disease (CKD).
2. Markers of nephrons damage
After kidney transplantation it is particularly important to monitor the biomarkers which allow to detect progress in disease process and determine which functional parts of kidney are going to be damaged, to enable application of a quick appropriate treatment (Lisowska-Myjak, 2010; Alachkar et al., 2010; Metzger et al., 2010). Administration of immunosuppressants for preventing renal graft rejection may lead to progressive damage to the renal tissue (interstitial fibrosis, tubular micro calcifications, atrophy of renal tubules) caused by high toxicity of suppressing drugs. Cyclosporine A(CsA), tacrolimus, mycophenolate mofetil, basiliximab, prednizon and sirolimus (rapamycin) are commonly used in immunosuppressive therapy following kidney transplantation. Cyclosporine A and tacrolimus generate immunosuppressive action by binding to cyclofiline and inhibiting the action of calcineurin 2, which stimulates proliferation and differentiation of lymphocytes T. Cyclosporine A inhibits synthesis of lymphokines by lymphocytes T. Lymphokines synthesized by lymphocytes T stimulate immunological system and have the ability to „kill” inflammatory and neoplastic cells. Mycophenolate mofetil selectively inhibits inosine monophosphate dehydrogenase, a basic enzyme in guanosine synthesis. Mycophenolate mofetil inhibits proliferation of lymphocytes T and B after stimulation with antigenes, cytokines and mitogens. Basiliximab similarly to Daclizumab, blocks receptors for IL-2.
Majority of renal pathological changes concern glomerules, proximal and distal tubules as well as vascular endothelium. At first renal proximal tubular cells (Fig.1.) demonstrating highest metabolic activity, possessing high amounts of mitochondries, lysosomes and peroxysomes are damaged. Remaining sections of nephron such as: Henle’s loop, distal tubules and collecting tubules are usually damaged later. There are numerous biomarkers that identify injury the area of the renal nephron, such as the glomerulus, the proximal, and the distal tubule.
2.1. Biomarkers of renal glomeruli
The oldest biomarkers of renal glomeruli injure are serum urea and creatinine as well as clearance of endogenic creatinine, which similarly to inulin (gold standard in GFR determination) is excreted to urine and not absorbed in renal tubules. Clearance of endogenic creatinine is 10-20% higher than clearance of inuline, which is a result trace excretion of creatinine by renal tubules (Finney et al., 2000).
2.2. Adhesion molecules connected podocytes with basement membrane
3. Biomarkers of proximal tubules
4. Markers of inflammatory reaction connected with acute renal failure
5. Proteins degrading extracellular matrix (ECM)
6. Immunological mediators of inflammatory state and fibrosis of renal tissue
6.1. Immunological markers of renal inflammatory state
6.2. Immunological markers of renal fibrosis
7. Tubular enzymes
Currently, in clinical diagnostic practice for renal parenchymal tubular impairment, assessment of urinary enzymes is used. Particular advantage of urinary enzymes determination is its localization in appropriate renal cells (glomeruli, tubules) and their organelles (cytoplasm, lysosomes, membranes), which may deliver detailed information concerning nature and dimension of the renal cells damage and an evaluation of their dysfunction or necrosis (Westhuyzen et al., 2003; Trof et al., 2006). Routine, simple, cheap and broadly available spectrophotometric methods are applied for measurement of urinary enzymes activity. An increase in urinary excretion of enzymes reflects damage of particular renal section (D‘Amico & Bazzi, 2003; Jung et al., 1986). Determination of urinary FBP-1,6, NAG, glutathione-S-transferase and pyruvate kinase has recently been recommended for the diagnosis of kidney disease and early detection of transplant rejection (Kotanko et al., 1997; Kotanko et al., 1986).
7.1. Enzymes of brush border membranes
7.2. Cytosolic enzymes
7.3. Renal lysosomal enzymes
8. Markers of renal ischemia/reperfusion injury
9. Biomarkers of dystal renal tubules
In the assessment of distal renal tubule dysfunction it is advised to examine urine osmolarity and/or determination Tamm-Horsfall glycoprotein as well as urinary kallikrein (Bhoola et al., 1992).
10. The future of biomarkers
Development of new technologies involved in molecular biology, analysis of m-RNA expression, proteomics and metabolomics create a possibility of discovery of new markers for early diagnosis of AKI and IF/TA. Relatively new method of microarrays (microarrays of cDNA and oligonuclotides- DNA chips) are sets of molecular probes attached to solid background in strictly determined order constituting two dimensional system of microscopic areas with defined sequences of nucleic acid. Microarray technology allow for detection of thousands of molecules of nucleic acids due to possibility of performing simultaneously many hybridization experiments (Dean et al., 2012). DNA microarrays technology permit for simultaneous monitoring expression of many genes (Scian et al., 2011). Identification of these genes constitute further step in earlier diagnosis and better prognosis of TA/IF(tubular atrophy/interstitial fibrosis).
New technologies and bioinformatics tools offer tremendous research possibilities which should make possible now and in the future precise monitoring of kidney graft, allow early detection and treatment of renal graft rejection and allow both for preventing and treatment of renal transplant complications as well as to improve number of long term patients survival.
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β2M,α1M | + | + | Johnston et al., 2011; Du et al., 2011; Câmara et al., 2009; |
Netrin-1 | + | Ramesh et al., 2010; Urbschat et al., 2011 | |
NGAL | + | Ramesh et al., 2010; Nauta et al., 2011; Przybyłowski et al., 2011; Halawa, 2011; Devarajan, 2011; Hall&Parikh, 2010; Du et al., 2011;Ting et al., 2012 | |
IL-16,IL-2,IL-6,IL-18,TNF | + | + | Alachkar er al., 2010; Halawa, 2011; Devarajan, 2011; Reinhold et al., 2012; Urbschat et al., 2011 |
KIM-1 | + | + | Nauta et al., 2011; Halawa, 2011; Devarajan,2011; Hall &Parikh, 2010; Du et al., 2011; Ting et al., 2012; Urbschat et al., 2011 |
NAG | + | Nauta et al. 2011; Câmara et al., 2009; Ting et al., 2012; Kuźniar et al., 2006; Alachkar et al., 2010 | |
H-FABP, L-FABP | + | + | Nauta et al., 2011; Przybylowskiet al., 2011 |
Cystatin C | + | Przybylowski et al., 2011; Hall &Parikh, 2010 | |
CXCL9,CXCL10 | + | + | Ho et al., 2011; Schaub et al., 2009; Jackson et al., 2011; Ting et al., 2012 |
alpha-GST, pi-GST | + | + | Câmara et al., 2009; |
GzmA,GzmB (granzyme) | + | van Ham et al., 2010; Peng et al., 2008; Oberbauer, 2008 | |
Galectin-3(Gal-3) | + | Dang et al., 2012 | |
Integrin α3, integrinβ2 | + | + | Srivastava et al., 2011 |
ANXA11 | + | + | Srivastavaet al., 2011 |
sVCAM | + | Reinhold et al., 2012 | |
MMP7, MMP-8 | + | Metzger et al., 2011; Ling et al., 2010 | |
LDH, ALP, γ-GT, AAP | + | Refaie et al., 2000; |
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OX40,OX40L,PD-1 | + | Afaneh et al., 2010 | |
HLA-DR | + | Ting et al., 2010 | |
CTGF | + | Yue et al., 2010; Bao et al., 2008 | |
uPA | + | Alachkar , 2012 | |
Leukocyte elastase (LE) | + | + | Zynek-Litwin et al., 2010 |
SERPING1 | + | Ling et al., 2010 | |
TIMP1 | + | Ling et al., 2010 | |
MIP-1delta, | + | + | Hu et al., 2009 |
Osteoprotegerin | + | + | Hu et al., 2009 |
VEGF | + | Peng et al., 2008 | |
fractalkine | + | Peng et al., 2008 | |
MCP-1 | + | Dubiński et al., 2008; Urbschat et al., 2011 | |
RBP | + | Kuźniar et al., 2006; Câmara et al., 2009 | |
Perforin | + | Oberbauer, 2008 | |
FOXP3 | + | Oberbauer, 2008 |
11. Conclusion
In this chapter we presented traditional and new biomarkers for diagnostics and monitoring condition of transplant kidneys. Urine is practical, easy to obtain, noninvasive material for diagnosis of kidney diseases. Numerous reports from molecular biology, genetics, proteomics and metabolomics disclosed an array of new markers specifically connected with damage of specific nephron segments in the course of successive steps of disease. Particular expectations are connected with proteins represented particular nephron section, or produced locally in the place of nephron damage. Presence of cytokines and chemokines in urine is an early sign of renal inflammatory state, due to influx of granulocytes to the damaged nephron area. Majority of traditional biomarkers, particularly enzymuria retains diagnostic value in an evaluation of the renal tubules function. Multitude of presented biomarkers suggest their limited diagnostic value. Discovering universal marker seems to be very difficult. However, it is potentially more fruitful to identity the putative biomarker proteins useful in diagnostics of kidney disease. Scientiscs are still looking for the “kidney troponin”. Actually, more than ten promising biomarkers for kidney damage have been identified. The most relevant and the best studied substances are neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury molecule-1 (KIM-1), beta-2 microglobulin (β2M), and interleukin-18 (IL- 18). In kidney allograft recipients, urinary KIM-1 expression provides prognostic information in relation to the rate of renal function decline, irrespective of the kidney pathology (Ting et al., 2012; Han et al., 2002; Szeto et al., 2010).
Validation of those kidney markers in various pathologic conditions is actually ongoing. However, the majority of publications reviewed are small cross-sectional studies, and there are only a handful of longitudinal studies. Another important point is that biomarkers only have clinical value if the results are reproducible. However none of the biomarkers reviewed here have been studied in more than 2 longitudinal trials so their clinical applicability needs to be confirmed in good quality, long-term, large longitudinal trials.
Among enzymes which retain high diagnostic value in diagnostics of renal diseases are: hexosaminidase and its isoenzyme B as a marker of the proximal tubular damage as well as AAP or GST as a marker of the tubular brush border membrane. Cytosolic FBP-1,6 is of great diagnostic value for assessment of graft function. It is commonly believed that appropriate panel of urinary proteins and enzymes may by a practical marker for evaluation of the nephron function of transplant kidney and prognosis of the renal allograft fate. In the future, discovery of new biomarkers and research techniques may change practical approach to treating patients with renal grafts. In summary we feel it is necessary for an international body to develop a renal marker utility grading system, to evaluate the usefulness of particular markers of nephron function and to make recommendations for the use of renal transplant markers, similar to those instilled for tumor markers (Hayes et al., 1996; Locker et al., 2006).
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