WO2025068313A1 - A method for early diagnosis, early prediction, monitoring or prediction of severity of reduced graft function in a kidney transplantation patient - Google Patents

Abstract

Subject matter of the present invention is a method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient comprising the steps of determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis and/ or the risk and/ or the severity of reduced graft function, wherein reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney.

Description

S75613WO BOEHMERT & BOEHMERT A method for early diagnosis, early prediction, monitoring or prediction of severity of reduced graft function in a kidney transplantation patient Subject matter of the present invention is a method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis and/ or risk and/ or the severity of reduced graft function, wherein said reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. Subject matter of the present invention is a method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with graft function and/ or risk and/ or the severity of reduced graft function, wherein said reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. Further subject matter of the present invention is a method patient stratification and/ or patient selection for early treatment of reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and ^ stratifying and/ or selecting said patient for early treatment of reduced graft function in correlation of said level of Pro-Enkephalin or fragments thereof in said sample, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. Further subject matter of the present invention is a method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to the present invention, wherein said method is used for patient stratification and/ or patient selection for early treatment of reduced graft function in a kidney transplantation patient. Further subject matter of the present invention is also a method for early diagnosis of graft function and/ or for early diagnosis and/ or early prediction of recovery from reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the recovery from of reduced graft function, wherein said reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. Further subject matter of the present invention is also a method for early diagnosis and/ or early prediction of immediate graft function (IGF) in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the graft function, wherein the graft function is immediate graft function (IGF) of the kidney. State of the Art Delayed graft function (DGF) is the term used to describe the failure of the transplanted kidney to function immediately after transplantation. It can be considered a form of acute kidney injury post- transplantation and is an important complication of kidney transplantation. The definition of DGF varies among transplant centers, although most define it as an acute kidney injury (AKI) that occurs in the first week after transplantation and requires a dialytic treatment (Yarlagadda et al. 2008. Nephrol Dial Transplant 23: 2995–3003). DGF is a frequent complication, with rates ranging between 25% and 30% (Mannon et al. 2018. Nephron Exp. Nephrol. 140: 94–98) and is still a major clinical challenge for the management of kidney transplant recipients. In fact, DGF is associated with higher rejection rates and worse short- and long-term outcomes (Bahl et al.2019. Curr. Opin. Organ Transplant.24: 82–86). The major risk factors involved in the development of DGF are ischemia–reperfusion injury (IRI), the source of donated kidney (deceased vs. living donation), the quality of the donated kidney, and the clinical conditions of the recipient (Ponticelli et al.2022. J. Pers. Med.12, 1557). In addition to the well-known complications of acute kidney injury and dialysis, DGF predisposes the graft to both acute and chronic rejection (Boom et al.2000. Kidney Int 58: 859–866) and increases the risk of chronic allograft nephropathy and premature graft loss (Giral-Classe et al. 1998. Kidney Int 54: 972–978). Poor function in the immediate post-operative period necessitates the use of dialysis from anywhere from days to months and therefore prolongs patient hospitalization and increases health care costs (Buchanan et al.2011. J Nephrol Therapeutic. S4: 001). Moreover, DGF complicates post-transplant management as an outpatient and increases morbidity. Kidneys for transplantation may be removed from living (relatives of recipients or unrelated donors) or deceased donors (brain-dead donors) with irreversible brain injury and persistent circulation maintained by supportive measures or donors after circulatory death. The risk of DGF is higher for deceased donors (Yasseri et al.2021. Urol. J.88: 185–189), although it is also present in living donors (Narayanan et al.2010. Am. J. Kidney Dis.56: 961–970). Brain-dead donors over the age of 60 or those aged 50–59 with two of these abnormalities (history of high blood pressure, final serum creatinine greater than 1.5 mg/dL (133 mmol/L), or cerebrovascular cause of death) are defined as expanded criteria donors (ECDs) (Metzger et al.2003. Am. J. Transplant.3 (Suppl. S4): 114–125). ECDs are often excluded from donation. When kidneys from ECDs are accepted, they often present DGF. Kidney allografts from ECDs have two-fold increased risk of DGF, more frequent acute rejection, and lower graft function in the long-term (Port et al. 2002. Transplantation 74: 1281–1286). Post-transplant renal function has historically been classified patients merely by the presence or absence of DGF. As a result, many patients may have significant injury but, by default, are considered to have “adequate” graft function if they avoid dialysis (Akkina et al. 2009. Am J Transplant 9: 1460–66). An intermediate phenotype, known as slow graft function (SGF), can be characterized by slower initial postoperative decline in serum creatinine (Cr) compared to immediate graft function (IGF) but without the need for dialysis (Moore et al. 2010. Transplantation 90: 1113–1116). However, SGF might influence early therapeutic decisions such as optimizing volume status, reducing calcineurin inhibitor exposure, avoiding nephrotoxins, and using calcium channel blocker (Peeters and Vanholder 2008. Transplantation 85: S31–37). SGF (SGF) is usually defined as no requirement of renal replacement therapy and a quotient < 0.7 of serum creatinin (SCr) of the difference of SCr on postoperative day 0 and day 7 devided by SCr on day 7. However, other slightly different definitions may be applied (e.g., the absolute level of SCr by a given postoperative day like SCr ≥3 mg/ld. On day 5 (Humar et al.1997. Clin Transplant 11: 623–27) or Cr ≥2.5 on day 7 (Zeraati et al. 2009. Transplant Proc 41: 2777–80) or an inadequate percentage reduction in SCr over a given period (e.g., a creatinine reduction ratio (CRR) of <30% between day 1 and 2 (Rodrigo et al.2004. Am J Transplant 4: 1163–69). Proenkephalin A is a precursor of the enkephalin family of endogenous opioids. It is a prohormone that is proteolytically processed to form several active pentapeptides like methionine-enkephalin (Met-Enk) and leucine-enkephalin (Leu-Enk) together with several other peptide fragments (enkelytin and C-terminal extended Met-Enk peptides). In addition to mature enkephalins, other peptides are produced, one of which is a stable proenkephalin peptide 119-159 (PENK 119-159). This peptide fragment levels in plasma/serum could serve as a surrogate measurement of systemic enkephalin synthesis, because proenkephalin is the predominant source of mature enkephalins. (Ernst et al., 2006. Peptides 27: 1835-1840). Enkephalins are widely secreted to act on locally expressed opioid receptors, specifically the δ opioid receptors. These opioid receptors are also widely expressed, with the highest density found in the kidney (Denning et al.2008. Peptides 29 (1): 83–921). After receptor binding, the biological effects of enkephalins include nociception, anesthetics, and cardiovascular regulation (Holaday 1983. Annu. Rev. Pharmacol. Toxicol. 23: 541–594). These δ opioid agonists stimulate natriuresis and diuresis (Sezen et al. 1998. J. Pharmacol. Exp. Ther.287 (1): 238–245). While several studies have demonstrated that elevated concentrations are associated with adverse outcomes, the association has in general been proportional to the change in renal function. Indeed, increased concentrations are associated with decreased renal function in several populations including sepsis (Marino et al. 2015. J Nephrol 28:717–724), heart failure (Ng et al.2017. J. Am. Coll. Cardiol.69 (1): 56–69; Matsue et al.2017. J. Card. Fail.23 (3): 231–239), cardiac surgery (Shah et al.2015. Clin. Nephrol.83 (1):29–35), and myocardial infarction (Ng et al. 2014. J. Am. Coll. Cardiol. 63 (3) (2014) 280–289). PENK 119-159 strongly correlates with the kidney function and measured GFR (Beunders et al. 2020 54(3): 308–314). Therefore, it was proposed as a biomarker for assessing kidney function in critically ill patients (Beunders et al.2017. Appl Lab Med 2(3): 400-412; Donato et al.2018. Clin Biochem 58: 72-77; Beunders et al. 2020 54(3): 308–314; Khorashadi et al. 2020. Nephron 144(12):655-661). It has been shown that plasma PENK is associated with kidney function as reflected by correlations with measured GFR in both renal transplant recipients and kidney donors one year after kidney transplantation. In addition, it was shown that PENK was independently associated with increased risk for late graft failure in renal transplant recipients using PENK levels measured at least one year after kidney transplantation (Kienecker et al.2017. Transplantation Direct 3: e190). However, nothing is known about PENK levels measured in newly transplanted patients (e.g., within hours or days after kidney transplantation). It was the surprising finding of the present invention that the levels of Pro-Enkephalin and fragments thereof, especially Pro-Enkephalin 119- 159 (MR-PENK, SEQ ID No.6), are suitable for early prediction and monitoring of reduced graft function in a kidney transplantation patient. Detailed Description Subject matter of the present invention is a method for early diagnosis and/ or early prediction and/ or monitoring a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis and/ or the risk and/ or severity of reduced graft function, wherein said reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. Subject matter of the present invention is a method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with graft function and/ or risk and/ or the severity of reduced graft function, wherein said reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. The term “early diagnosis” refers always to “early diagnosis of graft function” throughout the specification. Further subject matter of the present invention is a method patient stratification and/ or patient selection for early treatment of reduced graft function in a kidney patient transplantation comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and ^ stratifying and/ or selecting said patient for early treatment of reduced graft function in correlation of said level of Pro-Enkephalin or fragments thereof in said sample, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. Further subject matter of the present invention is a method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to the present invention, wherein said method is used for patient stratification and/ or patient selection for early treatment of reduced graft function in a kidney transplantation patient. Further subject matter of the present invention is also a method for early diagnosis and/ or early prediction of recovery from reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the recovery from of reduced graft function, wherein said reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. Further subject matter of the present invention is also a method for early diagnosis and/ or early prediction of immediate graft function (IGF) in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the graft function, wherein the graft function is immediate graft function (IGF) of the kidney. Further subject matter of the present invention is a method for early treatment of reduced graft function in a kidney transplantation patient, wherein the treatment is selected from the group comprising renal replacement therapy and/ or administration of a medicament and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs, wherein said patient is selected by a diagnostic method comprising the steps: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis and/or risk and/ or severity of reduced graft function, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. A further subject matter of the present invention is a medicament for use in early treatment of reduced graft function in a kidney transplantation patient, wherein said patient is selected by a diagnostic method comprising the steps: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis of reduced graft function and/ or the risk of reduced graft function, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. Surprisingly, it has been shown that Proenkephalin (PENK) or fragments thereof are powerful and highly significant biomarkers for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity reduced graft function in a kidney transplantation patient. Moreover, it has been shown to be especially useful for the early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of delayed graft function (DGF) in a kidney transplantation patient. It was a further surprising finding that levels of PENK or fragments thereof can be used in a kidney transplantation patient to predict short-term kidney function, especially a reduced kidney function (e.g. as reduced GFR) up to 30 days after kidney transplantation. The term “correlating”, as used herein in reference to the use of diagnostic and prognostic marker(s), (e.g. pro-enkephalin or fragments thereof), refers to comparing the presence or level of the marker(s) in a patient to its presence or amount in persons known to suffer from, or known to be at risk of, a given condition (e.g. DGF or SGF or reduced kidney function). A marker level in a patient sample can be compared to a level known to be associated with a specific diagnosis. The sample's marker level is said to have been correlated with a diagnosis; that is, the skilled artisan can use the marker level to determine whether the patient suffers from a specific type of a disease and respond accordingly. Moreover, the sample´s marker level can be compared to a marker level known to be associated with the prediction of a disease or an outcome of a disease (e.g. the development of a disease or condition, which may be for example DGF or SGF, the severity of a disease or condition or an improvement or worsening of a disease or condition, e.g. kidney function). The term "patient" as used herein refers to a living human or non-human organism. Preferably herein the patient is a human kidney transplantation patient. The term „kidney transplantation patient“ means a patient who is planned for kidney transplantation, a patient who is under kidney transplantation or a patient who already received kidney transplantation. The term “child” as used herein refers to a subject that is at the age of 18 years or below, more preferred at the age of 14 years or below, even more preferred at the age of 12 years or below, even more preferred at the age of 8 years or below, even more preferred at the age of 5 years or below, even more preferred at the age of 2 years or below, most preferred at the age of one year or below. The term “elevated level” means a level above a certain (predetermined) threshold level. The term “elevated” level may mean a level above a value that is regarded as being a reference and/ or threshold level. The term “diagnosing” in the context of the present invention relates to the recognition and (early) detection of a disease or clinical condition in a subject and may also comprise differential diagnosis. The term “early diagnosis” in the context of the present invention relates to the timepoint of the diagnosis of a disease or clinical condition in a subject which is before the usual time that the disease or clinical condition is diagnosed by gold standard methods. In case of the present invention “early diagnosis” means within 96 hours, preferably within 72 hours, more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation. In a preferred embodiment of the invention said early diagnosis means within 12 to 48 hours after kidney transplantation. In another preferred embodiment of the invention said early diagnosis means within 12 to 24 hours after kidney transplantation. In one embodiment of the present invention said early diagnosis means within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13 or 12 hours. In one embodiment “early diagnosis” is the “early diagnosis” of graft function of the kidney in a kidney transplantation patient. In a specific embodiment “early diagnosis” is the “early diagnosis” of reduced graft function of the kidney in a kidney transplantation patient. The term „prediction“ in the context of the present invention denotes a prediction of how a patient’s medical condition will progress. This may include an estimation of the chance of recovery or the chance (risk) of an adverse outcome (e.g., SGF or DGF, reduction in kidney function) for said patient. The term “early prediction” in the context of the present invention relates to the timepoint of the prediction of how a patient’s medical condition will progress which is before the usual time that a particular event happens (e.g., the occurrence of first symptoms of a disease). In case of the present invention “early prediction” means within 96 hours, preferably within 72 hours, more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation. In a preferred embodiment of the invention said early prediction means within 12 to 48 hours after kidney transplantation. In another preferred embodiment of the invention said early prediction means within 12 to 24 hours after kidney transplantation. In one embodiment of the present invention said early prediction means within 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13 or 12 hours. In one embodiment of the invention the term “early” in the context of diagnosis and/ or prediction means that at the timepoint of diagnosis of reduced graft function and/ or prediction of a risk of reduced graft function and/ or prediction of the severity of reduced graft function using Proenkephalin or fragments thereof, the biomarker serum creatinine (SCr) does not diagnose reduced graft function and/ or does not predict a risk of reduced graft function and/ or does not predict the severity of reduced graft function in a kidney transplantation patient. In a specific embodiment of the invention the term “early” in the context of diagnosis and/ or prediction means that at the timepoint of diagnosis of reduced graft function and/ or prediction of a risk of reduced graft function and/ or prediction of the severity of reduced graft function using Proenkephalin or fragments thereof (i) the level of serum creatinine (SCr) is still above a predetermined threshold level and/ or (ii) the relative change of SCr is a decrease of less than 50 %. In another specific embodiment of the invention, said predetermined threshold level of SCr is in the range between 1.5 and 4 mg/dL, more preferred in the range between 1.5 and 3 mg/dL, more preferred in the range between 1.5 and 2.5 mg/dL, most preferred said predetermined threshold is 2 mg/dL. In one embodiment the term “early” in the context of diagnosis and/ or prediction means within 96 hours, preferably within 72 hours, more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours and wherein (i) said level of SCr is above a predetermined threshold level and/ or (ii) the relative change of SCr is a decrease of less than 50 % in said kidney transplantation patient. In one embodiment of the invention the term “early” in the context of diagnosis and/ or prediction means that at a specific timepoint said level or relative change of Proenkephalin or fragments thereof diagnoses or predicts that said kidney transplantation patient does not have or will not develop reduced graft function but said level or relative change of SCr is still above a predetermined threshold or the decrease is less than 50%. If the doctor would only use the level or relative change of SCr, which is still above a predetermined threshold or the decrease is less than 50%, said kidney transplantation patient might be falsely diagnosed as having reduced graft function if the level or relative change of Proenkephalin or fragments thereof would not be considered within the first days after kidney transplantation. In one embodiment of the invention the prediction of kidney function in a kidney transplantation patient means prediction within 12 months, more preferred within 9 months, more preferred within 6 months, more preferred within 3 months, more preferred within 1 month, most preferred within 14 days. In a more specific embodiment of the invention the prediction of kidney function in a kidney transplantation patient means short-term prediction within 1 month, more preferred within 28 days, even more preferred within 21 days, most preferred within 14 days. The term „monitoring“ refers to controlling the development (detection of any changes) of a disease and or pathophysiological condition of a patient, e.g. risk or severity of a disease or condition or response to a therapy. Said patient monitoring or follow-up will be up to 28 days after kidney transplantation or until the graft function of the transplanted kidney is restored. Said follow-up measurements may be performed up to 7 days, preferably up to 14 days, more preferred up to 21 days, most preferred up to 28 days. In one embodiment said follow-up measurements may be performed until the kidney function is reserved. The term "monitoring the success of a therapy or intervention" in the context of the present invention refers to the control and/or adjustment of a therapeutic treatment of said patient. Predicting or monitoring the success of a therapy or intervention may be e.g., the prediction or monitoring the success of renal replacement therapy and/ or administration of a medicament and/ or adjustment of immunosuppressive drugs and/ or adjustment of nephrotoxic drugs using measurement of Pro-Enkephalin (PENK) or fragments thereof in a patient diagnosed and/ or being at risk of reduced graft function after kidney transplantation. Predicting or monitoring the success of a therapy or intervention may be e.g. the prediction or monitoring of the recovery of renal function in patients at risk of reduced graft function after kidney transplantation prior to and after renal replacement therapy and/or administration of a medicament and/ or adjustment of immunosuppressive drugs and/ or adjustment of nephrotoxic drugs using measurement of PENK or fragments thereof. “Before transplantation” is defined as any time up to 7 days before transplantation procedure starts. In a specific embodiment of the invention said sample taken before transplantation is obtained within 7 days, preferably 6 days, more preferred within 5 days, even more preferred within 4 days, even more preferred within 3 days, even more preferred within 48 hours, more preferred within 24 hours, preferably within 12 hours most preferred within 6 hours before transplantation procedure starts. The normal hospital procedure would be to take said sample within 24 hours before transplantation procedure starts. One embodiment of the invention is a method for predicting or monitoring the success of a therapy or intervention in a patient identified as having and/ or being at risk of reduced graft function after kidney transplantation, wherein a worsening or recovery of renal function prior to and/ or after therapy or intervention is predicted or monitored. The term “delayed graft function” (DGF) is defined as need for at least one dialysis within the first 7 days after kidney transplantation. The term “slow graft function” (SGF) is defined as no RRT therapy within 7 days after transplantation and quotient of creatinine on day 7/creatinine on day 0 < 0.7. Immediate graft function (IGF) was defined as no RRT within 7 days after transplantation and quotient of creatinine on day 7/creatinine on day 0 > 0.7. Reduced graft function is defined as either slow graft function (SGF) or delayed graft function (DGF). A major measure of kidney function is the glomerular filtration rate (GFR). GFR is equal to the total of the filtration rates of the functioning nephrons in the kidney and is considered the most useful index of kidney function in health and disease. The GFR is typically recorded in units of volume per time, e.g., milliliters per minute (mL/min). Glomerular filtration cannot be measured directly in humans; thus “true” GFR cannot be known with certainty. However, GFR can be assessed from clearance measurements (measured GFR [mGFR]) or serum levels of endogenous filtration markers (estimated GFR [eGFR]). The GFR can be measured by injecting inulin or the inulin-analog sinistrin into the blood stream (“measured GFR”). Using inulin to measure kidney function is the current "gold standard" for comparison with other means of estimating glomerular filtration rate. The contrast agents Iohexol and Iothalamate have become more popular alternatives to determine GFR and are considered to show sufficient accuracy to determine GFR (Soveri et al.2014. Am J Kidney Dis.64(3):411-24). The creatinine clearance rate (CCr or CrCl) is the volume of blood plasma that is cleared of creatinine per unit time and is a useful measure for approximating the GFR. Creatinine clearance exceeds GFR due to creatinine secretion, which can be blocked by cimetidine. Both GFR and CCr may be accurately calculated by comparative measurements of substances in the blood and urine or estimated by formulas using just a blood test result (eGFR and eCCr). The results of these tests are used to assess the excretory function of the kidneys. Estimated GFR (eGFR) is currently recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required (Levey et al.2020. Nat Rev Nephrol.16 (1): 51–64). There are several methods known in the art to determine eGFR. Estimated GFR may be calculated for example using CKD-EPI creatinine equation, CKD-EPI cystatin C equation or CKD-EPI creatinine cystatin C equation, the Modification of Diet in Renal Disease (MDRD) study equation, and Cockcroft-Gault equation (Santos and Martins 2015. World J Nephrol 4(3): 345-353). The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 (mL/min)/(1.73 m2) and no proteinuria 1) CKD1 – GFR above 90 (mL/min)/(1.73 m2) with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 (mL/min)/(1.73 m2) with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 (mL/min)/(1.73 m2) 4) CKD4 (severe) – GFR of 15 to 29 (mL/min)/(1.73 m2) 5) CKD5 kidney failure – GFR less than 15 (mL/min)/(1.73 m2). Therefore, kidney function in the context of the present invention may be determined by glomerular filtration rate (GFR), creatinine clearance rate (CCr), serum creatinine (SCr), serum cystatin C (CyC), urinalysis, blood urea nitrogen or urine output. GFR may be selected from estimated GFR (eGFR), true GFR or measured GFR (mGFR). In one embodiment of the invention a reduction of kidney function is predicted in said patient. In a specific embodiment of the invention said reduction of kidney function is determined by GFR. In a very specific embodiment of the invention a reduction of GFR below 60, preferably below 45, preferably below 30, most preferred below 15 is predicted. In one embodiment of the invention Proenkephalin or fragments thereof are diagnostic and/ or predictive of whether the patient is either having or developing slow graft function or delayed graft function. In other words, the level of Proenkephalin or fragments thereof can distinguish between a patient that has or will develop SGF and a patient that has or will develop DGF. In another embodiment of the invention the level of Proenkephalin or fragments thereof can distinguish between a patient that has or will develop SGF and a patient that has or will develop DGF, wherein (i) if said level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient is elevated above a predetermined threshold level, said patient has or is at risk of DGF, whereas (ii) if said level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient is below a predetermined threshold level, said patient has or is at risk of SGF. In a specific embodiment of the invention said predetermined threshold level to distinguish between a patient that has or will develop SGF and a patient that has or will develop DGF, is in the range between 100 and 500 pmol /L, more preferred in the range between 150 and 400 pmol/L, most preferred in the range between 200 and 350 pmol/L. In a more specific embodiment of the invention said patient will receive renal replacement therapy if delayed graft function is diagnosed and/ or predicted and will not receive renal replacement therapy if slow graft function is diagnosed or predicted. Severity of delayed graft function is defined as the number of days the patient needs renal replacement therapy. Delayed graft function can be classified into the severity groups defined as 0/1 (RRT only on day 0/day 1 = first 24h) which is low severity DGF, 2-7 (RRT ended between day 2 and day 7) which is medium severity and >7 (RRT lasted longer than day 7) which is high severity. A bodily fluid may be selected from the group comprising blood, serum, plasma, urine, cerebrospinal fluid (CSF), and saliva. In one embodiment of the invention the bodily fluid is selected from the group comprising whole blood, blood plasma, and blood serum. Pro-Enkephalin or fragments thereof are diagnostic and/ or predictive for reduced graft function and/ or predictive for the severity of reduced graft function in a kidney transplantation patient, wherein a sample from said patient is taken (a) at least once before and at least once after or (b) at least twice after kidney transplantation and wherein (i) an elevated level above a certain predetermined threshold or (ii) a relative change between the level of Pro-Enkephalin or fragments thereof in the samples either (a) taken before and after or twice after kidney transplantation is either a decrease of less than 50% or an increase, when the level of the earlier sample is set to 100%, is diagnostic and/ or predictive for reduced graft function and/ or predictive for the severity of reduced graft function in said patient. Pro-Enkephalin or fragments thereof are diagnostic and/ or predictive for delayed graft function and/ or predictive for the severity of delayed graft function in a kidney transplantation patient, wherein a sample of bodily fluid from said patient is taken at least once before and at least once after or at least twice after kidney transplantation and wherein (i) an elevated level above a certain predetermined threshold or (ii) a relative change between the level of Pro-Enkephalin or fragments thereof in the samples either taken before and after or twice after kidney transplantation is either a decrease of less than 50% or an increase, when the level of the earlier sample is set to 100%, is diagnostic and/ or predictive for delayed graft function and/ or predictive for the severity of delayed graft function in said patient. During follow-up measurements after kidney transplantation, (i) the level of Pro-Enkephalin or fragments thereof or (ii) a relative change of Pro-Enkephalin or fragments thereof correlates with the improvement or worsening of kidney function, wherein (i) a decrease of the level of Pro- Enkephalin or fragments thereof or (ii) a decrease of the relative change of Pro-Enkephalin or fragments thereof of more than 50% correlates with the improvement of kidney function and wherein (i) an increase of Pro-Enkephalin or fragments thereof or (ii) an either a decrease of less than 50% or an increase of the relative change of Pro-Enkephalin or fragments thereof correlates with a worsening of the kidney function in a patient that has been diagnosed and/ or predicted to be at risk of reduced graft function, in particular slow graft function or delayed graft function. During follow-up measurements after kidney transplantation, (i) the level of Pro-Enkephalin or fragments thereof or (ii) a relative change of Pro-Enkephalin or fragments thereof correlates with the success of the therapy or intervention, wherein (i) a decrease of the level of Pro-Enkephalin or fragments thereof or (ii) a decrease of the relative change of Pro-Enkephalin or fragments thereof of more than 50% correlates with a successful therapy or intervention and wherein (i) an increase of Pro-Enkephalin or fragments thereof or (ii) either a decrease of less than 50% or an increase of the relative change of Pro-Enkephalin or fragments thereof correlates with an unsuccessful therapy or intervention in a patient that has been diagnosed and/ or predicted to be at risk of reduced graft function, in particular slow graft function or delayed graft function. In one embodiment of the invention said therapy or intervention is renal replacement therapy, that is stopped and/ or withheld if said level of Proenkephalin or fragments thereof is below a predetermined threshold or the decrease of the relative change of Pro-Enkephalin or fragments thereof is more than 50%. A relative change of the level of a biomarker (e.g., the biomarker Proenkephalin or fragments thereof or the biomarker serum creatinine) is calculated between the level of the biomarker in a one sample taken at a specific timepoint and the level of the same biomarker in another sample taken after said first sample and when the level of the earlier sample is set to 100%. Pro-Enkephalin or fragments thereof are superior in comparison to other markers for early diagnosis and/ or early prediction of the risk and/ or monitoring the risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient (e.g., blood creatinine, creatinine clearance). Superiority means higher specificity, higher sensitivity, better correlation to clinical endpoints and at an earlier timepoint. Kidney function may be measured by GFR, creatinine clearance, SCr, cystatin C, urinalysis, blood urea nitrogen or urine output. In one embodiment of the invention said patient is in need of renal replacement therapy and/ or administration of a medicament and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs if a risk of reduced graft function is diagnosed and/ or predicted in said patient. Renal replacement therapy (RRT) replaces the normal blood-filtering function of the kidneys. relates to a therapy that is employed to replace the normal blood-filtering function of the kidneys. Renal replacement therapy may refer to dialysis (e.g. hemodialysis or peritoneal dialysis), hemofiltration, and hemodiafiltration. Such techniques are various ways of diverting the blood into a machine, cleaning it, and then returning it to the body. The hemodialysis, hemofiltration, and hemodiafiltration may be continuous or intermittent and can use an arteriovenous route (in which blood leaves from an artery and returns via a vein) or a venovenous route (in which blood leaves from a vein and returns via a vein). This results in various types of RRT. For example, the renal replacement therapy may be selected from the group of, but not limited to continuous renal replacement therapy (CRRT), continuous hemodialysis (CHD), continuous arteriovenous hemodialysis (CAVHD), continuous venovenous hemodialysis (CVVHD), continuous hemofiltration (CHF), continuous arteriovenous hemofiltration (CAVH or CAVHF), continuous venovenous hemofiltration (CVVH or CVVHF), continuous hemodiafiltration (CHDF), continuous arteriovenous hemodiafiltration (CAVHDF), continuous venovenous hemodiafiltration (CVVHDF), intermittent renal replacement therapy (IRRT), intermittent hemodialysis (IHD), intermittent venovenous hemodialysis (IVVHD), intermittent hemofiltration (IHF), intermittent venovenous hemofiltration (IVVH or IVVHF), intermittent hemodiafiltration (IHDF) and intermittent venovenous hemodiafiltration (IVVHDF). In a specific embodiment of the invention renal replacement therapy is selected from the group comprising dialysis (hemodialysis or peritoneal dialysis), hemofiltration, and hemodiafiltration. In a specific embodiment of the invention patients being at risk of reduced graft function after kidney transplantation, may be administered a medicament selected from the group comprising recombinant alkaline phosphatase, pegylated carboxyhemoglobin, relaxin, hepatocyte growth factor, mirocept, C1 esterase inhibitor. Immunosuppressive therapeutic drugs are selected from the group comprising interleukin 2 receptor antagonists, calcineurin inhibitors (e.g., cyclosporine A, tacrolimus), mammalian target of rapamycin inhibitor, corticosteroids (e.g., prednisolone), mycophenolate, sirolimus, azathioprine. Nephrotoxic medications may be selected from the group comprising calcineurin inhibitors for immunosuppression (e.g., cyclosporine A, tacrolimus), pain medications (e.g., Nonsteroidal anti- inflammatory drugs (NSAIDs) as ibuprofen, aspirin), anti-microbials (e.g., aminoglycosides, cephalosporins, penicillins, quinolones, rifampin and vancomycin), cholesterol-lowering statins, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and diuretics, chemotherapeutic agents (e.g,. cisplatin). In the context of the present invention, said adjustment of nephrotoxic medication and/ or adjustment of immunosuppressive therapy of a patient can involve initiation and/ or a change and/ or withdrawl of said nephrotoxic medication and/ or immunosuppressive therapeutic drugs. Said adjustment of nephrotoxic medication and/ or adjustment immunosuppressive therapeutic drugs may be a change in the dose, the administration route or regime or other parameters of nephrotoxic medication treatment. Furthermore, an adjustment in the treatment with nephrotoxic medication and/ or immunosuppressive therapeutic drugs may also and potentially additionally relate to a change in the one or more nephrotoxic agents and/ or immunosuppressive therapeutic drugs used for treating the patient. In some embodiments, a change can therefore relate to the replacement of one or more nephrotoxic medicaments and/ or immunosuppressive therapeutic drugs by one or more other agents. In a very specific embodiment of the invention said nephrotoxic medication and/ or immunosuppressive therapeutic drug is withdrawn from the patient. The terms Pro-Enkephalin, proenkephalin and PENK are used synonymously throughout the specification. Pro-Enkephalin has the following sequence: SEQ ID NO.1 (Pro-Enkephalin 1-243) ECSQDCATCSYRLVRPADINFLACVMECEGKLPSLKIWETCKELLQLSKPELPQDGTSTL RENSKPEESHLLAKRYGGFMKRYGGFMKKMDELYPMEPEEEANGSEILAKRYGGFMK KDAEEDDSLANSSDLLKELLETGDNRERSHHQDGSDNEEEVSKRYGGFMRGLKRSPQL EDEAKELQKRYGGFMRRVGRPEWWMDYQKRYGGFLKRFAEALPSDEEGESYSKEVPE MEKRYGGF MRF Fragments of Pro-Enkephalin, that may be determined in a bodily fluid, may be e.g. selected from the group of the following fragments: SEQ ID NO.2 (Synenkephalin, Pro-Enkephalin 1-73) ECSQDCATCSYRLVRPADINFLACVMECEGKLPSLKIWETCKELLQLSKPELPQDGTSTL RENSKPEESHLLA SEQ ID NO.3 (Met-Enkephalin) YGGFM SEQ ID NO.4 (Leu-Enkephalin) YGGFL SEQ ID NO.5 (Pro-Enkephalin 90-109) MDELYPMEPEEEANGSEILA SEQ ID NO 6: (Pro-Enkephalin 119-159, Mid-regional Pro-Enkephalin-fragment, MR-PENK) DAEEDDSLANSSDLLKELLETGDNRERSHHQDGSDNEEEVS SEQ ID NO.7 (Met-Enkephalin-Arg-Gly-Leu) YGGFMRGL SEQ ID NO.8 (Pro-Enkephalin 172-183) SPQLEDEAKELQ SEQ ID NO.9 (Pro-Enkephalin 193-203) VGRPEWWMDYQ SEQ ID NO.10 (Pro-Enkephalin 213-234) FAEALPSDEEGESYSKEVPEME SEQ ID NO.11 (Pro-Enkephalin 213-241) FAEALPSDEEGESYSKEVPEMEKRYGGF M SEQ ID NO.12 (Met-Enkephalin-Arg-Phe) YGGFMRF In one embodiment of the invention, it should be understood that the term fragments of Pro- Enkephalin also include Leu-Enkephalin and Met-Enkephalin. Determining the level of Pro-Enkephalin including Leu-Enkephalin and Met-Enkephalin or fragments thereof may mean that the immunoreactivity towards Pro-Enkephalin or fragments thereof including Leu-Enkephalin and Met-Enkephalin is determined. A binder used for determination of Pro-Enkephalin including Leu-Enkephalin and Met-Enkephalin or fragments thereof depending on the region of binding may bind to more than one of the above displayed molecules. This is clear to a person skilled in the art. This means in case a binder is used in the methods of the present invention that binds to a region within the amino acid sequence of Pro-Enkephalin (PENK) in a bodily fluid, then the terms “determining the level of Pro-Enkephalin (PENK) or fragments thereof in a bodily fluid obtained from said patient” are equivalent to “determining the level of immunoreactive analyte by using at least one binder that binds to a region within the amino acid sequence of Pro-Enkephalin (PENK) in a bodily fluid obtained from said patient”. In a specific embodiment a binder is used in the methods of the present invention that binds to a region within the amino acid sequence of Pro- Enkephalin (PENK) in a bodily fluid. In a specific embodiment said binder used in the methods of the present invention does bind to a region within the amino acid sequence of leu-enkephalin or met-enkephalin in a bodily fluid. In another specific embodiment of the present invention said at least one binder binds to mid-regional Pro-Enkephalin (MR-PENK) or a fragment thereof. Thus, according to the present invention the level of immunoreactive analyte by using at least one binder that binds to a region within the amino acid sequence of any of the above peptides and peptide fragments, (i.e. Pro-Enkephalin (PENK) and fragments according to any of the sequences 1 to 12), is determined in a bodily fluid obtained from said subject; and correlated to the specific embodiments of clinical relevance. In a more specific embodiment of the method according to the present invention the level of MR- PENK is determined (SEQ ID NO. 6: Pro-Enkephalin 119-159, Mid-regional Pro-Enkephalin- fragment, MR-PENK). In a more specific embodiment, the level of immunoreactive analyte by using at least one binder that binds to MR-PENK is determined and is correlated to the above- mentioned embodiments according to the invention. Thus, according to the present methods the level of immunoreactivity of the above binder is determined in a bodily fluid obtained from said patient. Level of immunoreactivity means the concentration of an analyte determined quantitatively, semi-quantitatively or qualitatively by a binding reaction of a binder to such analyte, where preferably the binder has an affinity constant for binding to the analyte of at least 108 M-1, and the binder may be an antibody or an antibody fragment or a non-Ig scaffold, and the binding reaction is an immunoassay. In a specific embodiment the level of Proenkephalin or fragments thereof is determined by using at least one binder that binds to a region within the amino acid sequence of a peptide selected from the group comprising Pro-Enkephalin or fragments thereof of at least 5 amino acids. In a specific embodiment said at least one binder binds to a region with the sequences selected from the group comprising SEQ ID No.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. In a specific embodiment said binder do not bind to enkephalin peptides Met-Enkephalin SEQ ID No: 3, and Leu-Enkephalin SEQ ID No: 4. In a specific embodiment said at least one binder binds to a region with the sequences selected from the group comprising SEQ ID No. 1, 2, 5, 6, 8, 9, 10 and 11. In another specific embodiment said at least one binder binds to a region with the sequences selected from the group comprising SEQ ID No.1, 2, 5, 6, 8 and 9. In another very specific embodiment said binder binds to Pro-Enkephalin 119-159, Mid-regional Pro-Enkephalin-fragment, MR-PENK (SEQ ID No.6). The before mentioned binder binds to said peptides in a bodily fluid obtained from said subject. Thus, subject matter of the present invention is method for early prediction of a risk or monitoring of a risk or prediction of the severity of reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Proenkephalin or fragments thereof by using at least one binder that binds to a region within the amino acid sequence of a peptide selected from the group comprising the Pro-Enkephalin peptides and fragments of SEQ ID No.1 to 12 in a bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof with the risk of and/ or severity of reduced graft function, wherein said reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. In one embodiment of the invention said binder is selected from the group comprising an antibody, an antibody fragment or a non-Ig-Scaffold binding to Pro-Enkephalin or fragments thereof of at least 5 amino acids. In a specific embodiment the level of Pro-Enkephalin or fragments thereof are measured with an immunoassay using antibodies or fragments of antibodies binding to Pro-Enkephalin or fragments thereof. An immunoassay that may be useful for determining the level of Pro-Enkephalin or fragments thereof of at least 5 amino acids may comprise the steps as outlined in Example 1. All thresholds and values have to be seen in correlation to the test and the calibration used according to Example 1. A person skilled in the art may know that the absolute value of a threshold might be influenced by the calibration used. This means that all values and thresholds given herein are to be understood in context of the calibration used in herein (Example 1). The above-mentioned threshold values might be different in other assays, if these have been calibrated differently from the assay system used in the present invention. Therefore, the above- mentioned threshold shall apply for such differently calibrated assays, accordingly, taking into account the differences in calibration. One possibility of quantifying the difference in calibration is a method comparison analysis (correlation) of the assay in question (e.g. assay for measurement of pro-enkephalin or fragments thereof) with the respective biomarker assay used in the present invention by measuring the respective biomarker (e.g. pro-enkephalin or fragments thereof) in samples using both methods. Another possibility is to determine with the assay in question, given this test has sufficient analytical sensitivity, the median biomarker level of a representative normal population, compare results with the median biomarker levels as described in the literature (e.g. Donato et al. 2018. Clin Biochem. 58: 72-77) and recalculate the calibration based on the difference obtained by this comparison. With the calibration used in the present invention, samples from normal (healthy) subjects (n=100) have been measured: median plasma pro-Enkephalin (penKid) (SEQ ID NO.6) was 48.1 pmol/L (interquartile range Q1-Q341.7 – 55.7 pmol/L) and the central 95% reference limit was 36 - 83 pmol/L (Donato et al. 2018. Clin Biochem. 58: 72- 77). Thus, in one embodiment of the invention said predetermined threshold level of Pro- Enkephalin or fragments thereof is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l. Thus, in one embodiment of the invention said predetermined threshold level of Pro-Enkephalin or fragments thereof is an x-fold of the median of the level of Proenkephalin or fragments thereof in a healthy population. In a specific embodiment of the invention the threshold level of Pro- Enkephalin or fragments thereof is in the range between the 1.0-fold and 15.6-fold, more preferred in the range between the 1.7-fold and 10.4-fold, even more preferred in the range between 2.1-fold and 8.3-fold, most preferred in the range between 3.1-fold and 6.2-fold of the median of the level of Proenkephalin or fragments thereof in a healthy population. A prerequisite of using the x-fold of e.g. the median (or a specific percentile) of the level of Proenkephalin or fragments thereof in a healthy population as a threshold level is that the assay used for the present invention and the differently calibrated assay (as mentioned above) are measuring in a linear way. Alternatively, the level of any of the above analytes may be determined by other analytical methods e.g. mass spectrometry. Mass spectrometric (MS) methods may include matrix assisted laser desorption/ ionization MS (MALDI-MS), liquid chromatography-mass spectrometry (LC- MS) and liquid-chromatography electrospray ionization MS (LC-ESI-MS). According to the invention the binder to Pro-Enkephalin is selected from the group consisting of antibodies e.g. IgG, a typical full-length immunoglobulin, or antibody fragments containing at least the F-variable domain of heavy and/or light chain as e.g. chemically coupled antibodies (fragment antigen binding) including but not limited to Fab-fragments including Fab minibodies, single chain Fab antibody, monovalent Fab antibody with epitope tags, e.g. Fab-V5Sx2; bivalent Fab (mini-antibody) dimerized with the CH₃ domain; bivalent Fab or multivalent Fab, e.g. formed via multimerization with the aid of a heterologous domain, e.g. via dimerization of dHLX domains, e.g. Fab-dHLX-FSx2; F(ab‘)2-fragments, scFv-fragments, multimerized multivalent or/and multi- specific scFv-fragments, bivalent and/or bispecific diabodies, BITE® (bispecific T-cell engager), trifunctional antibodies, polyvalent antibodies, e.g. from a different class than G; single-domain antibodies, e.g. nanobodies derived from camelid or fish immunoglobulines. In a specific embodiment the level of Pro-Enkephalin or fragments thereof are measured with an assay using binders selected from the group comprising aptamers, non-Ig scaffolds as described in greater detail below binding to Pro-Enkephalin or fragments thereof. Binder that may be used for determining the level of Pro-Enkephalin or fragments thereof exhibit an affinity constant to Pro-Enkephalin of at least 107 M-1, preferred 108 M-1, preferred affinity constant is greater than 109 M-1, most preferred greater than 1010 M-1. A person skilled in the art knows that it may be considered to compensate lower affinity by applying a higher dose of compounds and this measure would not lead out-of-the-scope of the invention. Binding affinity may be determined using the Biacore method, offered as service analysis e.g. at Biaffin, Kassel, Germany (http://www.biaffin.com/de/). In addition to antibodies other biopolymer scaffolds are well known in the art to complex a target molecule and have been used for the generation of highly target specific biopolymers. Examples are aptamers, spiegelmers, anticalins and conotoxins. Non-Ig scaffolds may be protein scaffolds and may be used as antibody mimics as they are capable to bind to ligands or antigens. Non-Ig scaffolds may be selected from the group comprising tetranectin-based non-Ig scaffolds (e.g. described in US 2010/0028995), fibronectin scaffolds (e.g. described in EP 1266025; lipocalin- based scaffolds (e.g. described in WO 2011/154420); ubiquitin scaffolds (e.g. described in WO 2011/073214), transferring scaffolds (e.g. described in US 2004/0023334), protein A scaffolds (e.g. described in EP 2231860), ankyrin repeat based scaffolds (e.g. described in WO 2010/060748), microproteins preferably microproteins forming a cystine knot) scaffolds (e.g. described in EP 2314308), Fyn SH3 domain based scaffolds (e.g. described in WO 2011/023685) EGFR-A-domain based scaffolds (e.g. described in WO 2005/040229) and Kunitz domain based scaffolds (e.g. described in EP 1941867). The threshold level is a level, which allows for allocating the patient into a group of patients who have been diagnosed and/ or are being at risk of an adverse event (e.g., reduced graft function), or into a group of patients who have not been diagnosed and/ or are not being at risk of an adverse event, or into a severity group (e.g., of delayed graft function). Thus, the threshold level shall allow for differentiating between a patient who is diagnosed and/ or is at risk of an adverse event and a patient who is not diagnosed and/ or at risk of an adverse event. It is known in the art how threshold levels can be determined. Threshold levels are predetermined values and are set to meet routine requirements in terms of, e.g., specificity and/or sensitivity. These requirements can vary. It may for example be that sensitivity or specificity, respectively, has to be set to certain limits, e.g., 80%, 90%, 95% or 98%, respectively. The sensitivity and specificity of a diagnostic and/or prognostic test depends on more than just the analytical "quality" of the test, they also depend on the definition of what constitutes an abnormal result. In practice, Receiver Operating Characteristic curves (ROC curves), are typically calculated by plotting the value of a variable versus its relative frequency in "reference group" (i.e. patients who do not develop reduced graft function after kidney transplantation) and "disease" populations (i.e. patients developing reduced graft function after kidney transplantation). For any particular marker, a distribution of marker levels for patients with and without developing reduced graft function will likely overlap. Under such conditions, a test does not absolutely distinguish patients with and without developing reduced graft function (e.g., slow graft function or delayed graft function) with 100% accuracy, and the area of overlap indicates where the test cannot distinguish normal from disease. A threshold is selected, above which (or below which, depending on how a marker changes with the disease) the test is considered to be abnormal and below which the test is considered to be normal. The area under the ROC curve is a measure of the probability that the perceived measurement will allow correct identification of a condition. ROC curves can be used even when test results do not necessarily give an accurate number. As long as one can rank results, one can create a ROC curve. For example, results of a test on "disease" samples might be ranked according to degree (e.g. l=low, 2=normal, and 3=high). This ranking can be correlated to results in the "reference" group, and a ROC curve created. These methods are well known in the art (See, e.g., Hanley et al.1982. Radiology 143: 29-36). Preferably, ROC curves result in an AUC of greater than about 0.5, more preferably greater than about 0.7, still more preferably greater than about 0.8, even more preferably greater than about 0.85, and most preferably greater than about 0.9. The term "about" in this context refers to +/- 5% of a given measurement. A reference group may be a healthy population, e.g., with no signs and symptoms of a disease. In a further aspect of the invention, a reference group may be a population of kidney transplantation patients, in particular without developing reduced graft function (e.g., patients with immediate graft function). A reference group may consist of more than one reference subjects. The horizontal axis of the ROC curve represents (1 -specificity), which increases with the rate of false positives. The vertical axis of the curve represents sensitivity, which increases with the rate of true positives. Thus, for a particular cut-off threshold selected, the value of (1 -specificity) may be determined, and a corresponding sensitivity may be obtained. The area under the ROC curve is a measure of the probability that the measured marker level will allow correct identification of a disease or condition. Thus, the area under the ROC curve can be used to determine the effectiveness of the test. For time-to-event data – as eg in mortality risk prediction – threshold levels can further be obtained for instance from a Kaplan-Meier analysis, where the occurrence of a disease is correlated with e.g. the tertiles, quartiles, quintiles of the markers (e.g. kidney markers, cardiovascular markers) in the population. There are also equivalent methods available to the ROC methods described before, based on i.e. time-dependent ROC analysis or generalizations of the area under the ROC curve (C index). Other preferred threshold values are for instance the 90th, 95th or 99th percentile of a normal population. By using a higher percentile than the 75th percentile, one reduces the number of false positive subjects identified, but one might miss to identify subjects, who are at moderate, albeit still increased risk. Thus, one might adopt the threshold value depending on whether it is considered more appropriate to identify most of the subjects at risk at the expense of also identifying "false positives", or whether it is considered more appropriate to identify mainly the subjects at high risk at the expense of missing several subjects at moderate risk. For example, the 75th percentile, more preferred the 90th percentile, even more preferred a 95th percentile, most preferred the 99th percentile values can be used for the upper limits of the normal range. In addition to the normal range, other methods may be used to determine thresholds for a specific indication, depending on the intended use and application/clinical setting. Such methods include eg the Youden optimum, thresholds that maximise overall accuracy, the odds ratio, or the positive or negative predictive value. In some situations, thresholds achieving a pre-specified level of sensitivity or specificity (eg 80%, 90%, 95% or 99%) can be appropriate for the clinical application. The choice of methods depends on the clinical application, which weights the costs of false positive and false negative results based on the test result consequences for the patient and the health care system, as well as the clinical need. Finally, multiple approaches may be combined to define a consensus threshold. The threshold level may vary depending on various physiological parameters such as age, gender or sub-population, as well as on the means used for the determination of Pro-Enkephalin and fragments thereof referred to herein. In a specific embodiment of the invention, said threshold levels are age-dependent. The values for MR-PENK (Proenkephalin 119-159; SEQ ID N: 6) revealed the use of more than one threshold value depending on the age of the subject. The threshold values decreased with increasing age of the patients. In one embodiment of the invention said predetermined threshold level of Pro-Enkephalin or fragments thereof is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l. In a specific embodiment said fragment of Pro-Enkephalin is MR-PENK (PENK 119-159, SEQ ID NO.6). In another specific embodiment of the invention said predetermined threshold level of MR-PENK (PENK 119-159, SEQ ID NO.6) is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l. Said threshold levels may be similar for other Pro-Enkephalin fragments that are derived from the precursor Proenkephalin in a 1:1 molar ratio. As mature Met-Enkephalin is encoded by the Pro- Enkephalin precursor in a 6:1 molar ratio, meaning that 6 molecules of Met-Enkephalin are derived from one precursor, said threshold for Met-Enkephalin is six-times higher compared to the threshold level of MR-PENK. In a very specific embodiment of the invention said predetermined threshold level of Proenkephalin or fragments thereof, in particular MR-PENK (PENK 119-159, SEQ ID NO.6), is 300 pmol/L if measured up to 24 hours after kidney transplantation. In another very specific embodiment of the invention said predetermined threshold level of Proenkephalin or fragments thereof, in particular MR-PENK (PENK 119-159, SEQ ID NO.6) is 200 pmol/L if measured between more than 24 hours and up to 48 hours after kidney transplantation. In another embodiment of the invention the level of Pro-Enkephalin or fragments thereof is determined in a sample of bodily fluid obtained from said patient before and after kidney transplantation. Said sample, which is obtained after kidney transplantation, is taken in the range between 3 and 96 hours, more preferred in the range between 6 and 72 hours, even more preferred in the range between 9 and 48 hours, most preferred in the range between 12 and 24 hours after kidney transplantation. In a more specific embodiment of the invention said sample, which is obtained after kidney transplantation, is taken within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation. In one embodiment of the invention the level of Pro-Enkephalin or fragments thereof may be determined more than 96 hours after kidney transplantation as follow-up. In one embodiment of the invention a relative change of the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid taken (i) at least once before and at least once or (ii) at least twice after kidney transplantation is calculated and correlated with the diagnosis and/ or the risk of and/ or the severity of reduced graft function of the kidney of said patient. In a specific embodiment of the invention said relative change of the level of Pro-Enkephalin or fragments thereof is an insufficient decrease or even an increase. In another specific embodiment a reduced graft function of the kidney in said patient is diagnosed and/ or predicted if said decrease is less than 35%, preferably less than 40%, even more preferred less than 45%, most preferred less than 50% when the level of the earlier sample is set to 100%. In a specific embodiment of the invention reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient if said relative change between the level of Pro- Enkephalin or fragments thereof in the samples either taken (i) at least once before and at least once after or (ii) at least twice after kidney transplantation is either a decrease of less than 50% or an increase, when the level of the earlier sample is set to 100%. If said samples are taken for example once before (sample 1) and once (e.g., 24 hours) after kidney transplantation (sample 2) and a relative change of the level of Pro-Enkephalin or fragments thereof is calculated between sample 1, which is set 100% and sample 2, resulting in a decrease of less than 50% or an increase, said patient is diagnosed and/ or predicted to be at risk of reduced graft function. Then a third sample may be taken after sample 2 (e.g., 48 hours) after kidney transplantation for monitoring of the patient. Again, a relative change of the level of Pro- Enkephalin or fragments thereof is calculated between sample 2, which is now set 100% and sample 3. Subject matter of the invention is further a medicament for use in early treatment of reduced graft function in a kidney transplantation patient, wherein said patient is selected by a diagnostic method comprising the steps: - determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and - correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis of reduced graft function and/ or the risk of reduced graft function, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. In one embodiment said medicament is selected from the group comprising recombinant alkaline phosphatase, pegylated carboxyhemoglobin, relaxin, hepatocyte growth factor, mirocept, C1 esterase inhibitor. In one specific embodiment the level of Pro Enkephalin or fragments thereof is measured with an immunoassay and said binder is an antibody, or an antibody fragment binding to Pro-Enkephalin or fragments thereof. In one specific embodiment the assay used comprises two binders that bind to two different regions within the region of Pro-Enkephalin that is amino acid 133-140 (LKELLETG, SEQ ID No. 13) and amino acid 152-159 (SDNEEEVS, SEQ ID No.14), wherein each of said regions comprises at least 4 or 5 amino acids. In one embodiment of the invention the assay sensitivity for determining Pro-Enkephalin or fragments in a sample is < 15 pmol/L, preferably < 10 pmol/L and most preferred < 6 pmol/L. Subject matter of the present invention is the use of at least one binder that binds to a region within the amino acid sequence of a peptide selected from the group comprising the peptides and fragments of SEQ ID No.1 to 12 in a bodily fluid obtained from said subject in a method for early prediction of a risk or monitoring of a risk or prediction of the severity of reduced graft function in a kidney transplantation patient. In one embodiment of the invention said binder is selected from the group comprising an antibody, an antibody fragment or a non-Ig scaffold binding to Pro-Enkephalin or fragments thereof of at least 5 amino acids. In a specific embodiment said at least one binder binds to a region with the sequences selected from the group comprising SEQ ID No.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. In a specific embodiment said binder binds to enkephalin peptides met-enkephalin (SEQ ID No: 3), and leu-enkephalin (SEQ ID No: 4). In a specific embodiment said at least one binder binds to a region with the sequences selected from the group comprising SEQ ID No. 1, 2, 5, 6, 8, 9, 10 and 11. In another specific embodiment said at least one binder binds to a region with the sequences selected from the group comprising SEQ ID No. 1, 2, 5, 6, 8 and 9. In another very specific embodiment said binder binds to Pro-Enkephalin 119-159, mid-regional Pro-Enkephalin- fragment, MR-PENK (SEQ ID No.6). In a more specific embodiment the at least one binder binds to a region within the amino acid sequence of Pro-Enkephalin 119-159, mid-regional Pro-Enkephalin fragment, MR-PENK (SEQ ID No. 6) in a bodily fluid obtained from said subject, more specifically to amino acid 133-140 (LKELLETG, SEQ ID No. 13) and/or amino acid 152-159 (SDNEEEVS, SEQ ID No. 14), wherein each of said regions comprises at least 4 or 5 amino acids. Said additionally at least one clinical parameter that may be determined is selected from the group comprising: alanine aminopeptidase, alkaline phosphatase, gamma-glutamyl transpeptidase, calprotectin, C-C motif chemokine ligand 14, chitinase 3-like protein 1, hepatocyte growth factor, hepcidin, IL-18, beta-trace protein (BTP), cystatin C, KIM-1, TIMP-2, IGFBP-7, blood urea nitrogen (BUN), NGAL, liver-type fatty acid binding protein, monocyte chemoattractant peptide- 1, Creatinine Clearance, serum Creatinine (SCr), urea, metrin-1, osteopontin, retinol binding protein, tumor necrosis factor, and Apache Score. In one embodiment of the invention said method is performed more than once in order to monitor the risk of said patient or in order to monitor the course of treatment of said kidney transplantation patient. In one specific embodiment said monitoring is performed in order to evaluate the response of said patient to preventive and/or therapeutic measures taken. In one embodiment of the invention the method is used in order to stratify said patients into risk groups. Said patient may be stratified into a risk group of low, intermediate or high risk of reduced graft function. Said patient may be stratified into a low, intermediate or high-risk group for slow graft function and/ or delayed graft function. Subject matter of the invention is further an assay for determining Pro-Enkephalin and Pro- Enkephalin fragments in a sample comprising two binders that bind to two different regions within the region of Pro-Enkephalin that is amino acid 133-140 (LKELLETG, SEQ ID NO.13) and amino acid 152-159 (SDNEEEVS, SEQ ID NO.14), wherein each of said regions comprises at least 4 or 5 amino acids. In one embodiment of the invention, it may be a so-called POC-test (point –of-care), that is a test technology which allows performing the test within less than 1 hour near the patient without the requirement of a fully automated assay system. One example for this technology is the immunochromatographic test technology. In one embodiment of the invention such an assay is a sandwich immunoassay using any kind of detection technology including but not restricted to enzyme label, chemiluminescence label, electrochemiluminescence label, preferably a fully automated assay. In one embodiment of the invention such an assay is an enzyme labeled sandwich assay. Examples of automated or fully automated assay comprise assays that may be used for one of the following systems: Roche Elecsys®, Abbott Architect®, Siemens Centauer®, Brahms Kryptor®, Biomerieux Vidas®, Alere Triage®. A variety of immunoassays are known and may be used for the assays and methods of the present invention, these include: radioimmunoassays ("RIA"), homogeneous enzyme-multiplied immunoassays ("EMIT"), enzyme linked immunoadsorbent assays ("ELISA"), apoenzyme reactivation immunoassay ("ARIS"), dipstick immunoassays and immuno-chromatography assays. In one embodiment of the invention at least one of said two binders is labeled in order to be detected. The preferred detection methods comprise immunoassays in various formats such as for instance radioimmunoassay (RIA), chemiluminescence- and fluorescence-immunoassays, Enzyme-linked immunoassays (ELISA), Luminex-based bead arrays, protein microarray assays, and rapid test formats such as for instance immunochromatographic strip tests. In a preferred embodiment said label is selected from the group comprising chemiluminescent label, enzyme label, fluorescence label, radioiodine label. The assays can be homogenous or heterogeneous assays, competitive and non-competitive assays. In one embodiment, the assay is in the form of a sandwich assay, which is a non-competitive immunoassay, wherein the molecule to be detected and/or quantified is bound to a first antibody and to a second antibody. The first antibody may be bound to a solid phase, e.g. a bead, a surface of a well or other container, a chip or a strip, and the second antibody is an antibody which is labeled, e.g. with a dye, with a radioisotope, or a reactive or catalytically active moiety. The amount of labeled antibody bound to the analyte is then measured by an appropriate method. The general composition and procedures involved with “sandwich assays” are well-established and known to the skilled person. In another embodiment the assay comprises two capture molecules, preferably antibodies which are both present as dispersions in a liquid reaction mixture, wherein a first labelling component is attached to the first capture molecule, wherein said first labelling component is part of a labelling system based on fluorescence- or chemiluminescence-quenching or amplification, and a second labelling component of said marking system is attached to the second capture molecule, so that upon binding of both capture molecules to the analyte a measurable signal is generated that allows for the detection of the formed sandwich complexes in the solution comprising the sample. In another embodiment, said labeling system comprises rare earth cryptates or rare earth chelates in combination with fluorescence dye or chemiluminescence dye, in particular a dye of the cyanine type. In the context of the present invention, fluorescence based assays comprise the use of dyes, which may for instance be selected from the group comprising FAM (5-or 6-carboxyfluorescein), VIC, NED, Fluorescein, Fluorescein-isothiocyanate (FITC), IRD-700/800, Cyanine dyes, such as CY3, CY5, CY3.5, CY5.5, Cy7, Xanthen, 6-Carboxy-2’,4’,7’,4,7-hexachlorofluorescein (HEX), TET, 6-Carboxy-4’,5’-dichloro-2’,7’-dimethodyfluorescein (JOE), N,N,N’,N’-Tetramethyl-6-carboxy- rhodamine (TAMRA), 6-Carboxy-X-rhodamine (ROX), 5-Carboxyrhodamine-6G (R6G5), 6- carboxyrhodamine-6G (RG6), Rhodamine, Rhodamine Green, Rhodamine Red, Rhodamine 110, BODIPY dyes, such as BODIPY TMR, Oregon Green, Coumarines such as Umbelliferone, Benzimides, such as Hoechst 33258; Phenanthridines, such as Texas Red, Yakima Yellow, Alexa Fluor, PET, Ethidiumbromide, Acridinium dyes, Carbazol dyes, Phenoxazine dyes, Porphyrine dyes, Polymethin dyes, and the like. In the context of the present invention, chemiluminescence based assays comprise the use of dyes, based on the physical principles described for chemiluminescent materials in (Kirk-Othmer, Encyclopedia of chemical technology, 4th ed., executive editor, J. I. Kroschwitz; editor, M. Howe- Grant, John Wiley & Sons, 1993, vol.15, p.518-562, incorporated herein by reference, including citations on pages 551-562). Chemiluminescent label may be acridinium ester label, steroid labels involving isoluminol labels and the like. Preferred chemiluminescent dyes are acridiniumesters. As mentioned herein, an “assay” or “diagnostic assay” can be of any type applied in the field of diagnostics. Such an assay may be based on the binding of an analyte to be detected to one or more capture probes with a certain affinity. Concerning the interaction between capture molecules and target molecules or molecules of interest, the affinity constant is preferably greater than 108 M-1. In the context of the present invention, “binder molecules” are molecules which may be used to bind target molecules or molecules of interest, i.e. analytes (i.e. in the context of the present invention PENK and fragments thereof), from a sample. Binder molecules must thus be shaped adequately, both spatially and in terms of surface features, such as surface charge, hydrophobicity, hydrophilicity, presence or absence of lewis donors and/or acceptors, to specifically bind the target molecules or molecules of interest. Hereby, the binding may for instance be mediated by ionic, van-der-Waals, pi-pi, sigma-pi, hydrophobic or hydrogen bond interactions or a combination of two or more of the aforementioned interactions between the capture molecules and the target molecules or molecules of interest. In the context of the present invention, binder molecules may for instance be selected from the group comprising a nucleic acid molecule, a carbohydrate molecule, a PNA molecule, a protein, an antibody, a peptide or a glycoprotein. Preferably, the binder molecules are antibodies, including fragments thereof with sufficient affinity to a target or molecule of interest, and including recombinant antibodies or recombinant antibody fragments, as well as chemically and/or biochemically modified derivatives of said antibodies or fragments derived from the variant chain with a length of at least 12 amino acids thereof. Chemiluminescent label may be acridinium ester label, steroid labels involving isoluminol labels and the like. Enzyme labels may be lactate dehydrogenase (LDH), creatine kinase (CPK), alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), acidic phosphatase, glucose- 6-phosphate dehydrogenase, horse radish peroxidase (HRP) and so on. In one embodiment of the invention at least one of said two binders is bound to a solid phase as magnetic particles, and polystyrene surfaces. In one embodiment of the assays for determining Pro-Enkephalin or Pro-Enkephalin fragments in a sample according to the present invention such assay is a sandwich assay, preferably a fully automated assay. It may be an ELISA fully automated or manual. It may be a so-called POC-test (point-of-care). Examples of automated or fully automated assay comprise assays that may be used for one of the following systems: Roche Elecsys®, Abbott Architect®, Siemens Centauer®, Brahms Kryptor®, Biomerieux Vidas®, Alere Triage®, Ortho Vitros®. Examples of test formats are provided above. In one embodiment of the assays for determining Pro-Enkephalin or Pro-Enkephalin fragments in a sample according to the present invention at least one of said two binders is labeled in order to be detected. Examples of labels are provided above. In one embodiment of the assays for determining Pro-Enkephalin or Pro-Enkephalin fragments in a sample according to the present invention at least one of said two binders is bound to a solid phase. Examples of solid phases are provided above. In one embodiment of the assays for determining Pro-Enkephalin or Pro-Enkephalin fragments in a sample according to the present invention said label is selected from the group comprising chemiluminescent label, enzyme label, fluorescence label, radioiodine label. A further subject of the present invention is a kit comprising an assay according to the present invention wherein the components of said assay may be comprised in one or more container. In one embodiment subject matter of the present invention is a point-of-care device for performing a method according to the invention, wherein said point-of-care device comprises at least one antibody or antibody fragment directed to either amino acid 133-140 (LKELLETG, SEQ ID No. 13) or amino acid 152-159 (SDNEEEVS, SEQ ID NO.14), wherein each of said regions comprises at least 4 or 5 amino acids. In one embodiment subject matter of the present invention is a point-of-care device for performing a method according to the invention, wherein said point-of-care device comprises at least two antibodies or antibody fragments directed to amino acid 133-140 (LKELLETG, SEQ ID No.13) and amino acid 152-159 (SDNEEEVS, SEQ ID No.14), wherein each of said regions comprises at least 4 or 5 amino acids. In one embodiment subject matter of the present invention is a kit or performing a method according to the invention, wherein said point-of-care device comprises at least one antibody or antibody fragment directed to either amino acid 133-140 (LKELLETG, SEQ ID No.13) or amino acid 152-159 (SDNEEEVS, SEQ ID No.14), wherein each of said regions comprises at least 4 or 5 amino acids. In one embodiment subject matter of the present invention is a kit for performing a method according to the invention, wherein said point-of-care device comprises at least two antibodies or antibody fragments directed to amino acid 133-140 (LKELLETG, SEQ ID No.13) and amino acid 152-159 (SDNEEEVS, SEQ ID No. 14), wherein each of said regions comprises at least 4 or 5 amino acids. The term “antibody” generally comprises monoclonal and polyclonal antibodies and binding fragments thereof, in particular Fc-fragments as well as so called “single-chain-antibodies” (Bird et al. 1988), chimeric, humanized, in particular CDR-grafted antibodies, and dia- or tetrabodies (Holliger et al.1993). Also comprised are immunoglobulin-like proteins that are selected through techniques including, for example, phage display to specifically bind to the molecule of interest contained in a sample. In this context the term “specific binding” refers to antibodies raised against the molecule of interest or a fragment thereof. An antibody is considered to be specific, if its affinity towards the molecule of interest or the aforementioned fragment thereof is at least preferably 50-fold higher, more preferably 100-fold higher, most preferably at least 1000-fold higher than towards other molecules comprised in a sample containing the molecule of interest. It is well known in the art how to make antibodies and to select antibodies with a given specificity. An antibody or fragment according to the present invention is a protein including one or more polypeptides substantially encoded by immunoglobulin genes that specifically binds an antigen. The recognized immunoglobulin genes inc1ude the kappa, lambda, alpha (IgA), gamma (IgG1, IgG2, IgG3, IgG4), delta (IgD), epsilon (IgE) and mu (IgM) constant region genes, as well as the myriad immunoglobulin variable region genes. Full-length immunoglobulin light chains are generally about 25 Kd or 214 amino acids in length. Full-length immunoglobulin heavy chains are generally about 50 Kd or 446 amino acid in length. Light chains are encoded by a variable region gene at the NH2-terminus (about 110 amino acids in length) and a kappa or lambda constant region gene at the COOH-terminus. Heavy chains are similarly encoded by a variable region gene (about 116 amino acids in length) and one of the other constant region genes. The basic structural unit of an antibody is generally a tetramer that consists of two identical pairs of immunoglobulin chains, each pair having one light and one heavy chain. In each pair, the light and heavy chain variable regions bind to an antigen, and the constant regions mediate effector functions. Immunoglobulins also exist in a variety of other forms inc1uding, for example, Fv, Fab, and (Fab')2, as well as bifunctional hybrid antibodies and single chains (e.g., Lanzavecchia et al. 1987. Eur. J. Immunol.17: 105; Huston et al.1988. Proc. Natl. Acad. Sci. U.S.A., 85: 5879-5883; Bird et al.1988. Science 242: 423-426; Hood et al.1984, Immunology, Benjamin, N.Y., 2nd ed.; Hunkapiller and Hood 1986. Nature 323:15-16). An immunoglobulin light or heavy chain variable region inc1udes a framework region interrupted by three hypervariable regions, also called complementarity determining regions (CDR's) (see, Sequences of Proteins of Immunological Interest, E. Kabat et al.1983, U.S. Department of Health and Human Services). As noted above, the CDRs are primarily responsible for binding to an epitope of an antigen. An immune complex is an antibody, such as a monoclonal antibody, chimeric antibody, humanized antibody or human antibody, or functional antibody fragment, specifically bound to the antigen. Chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from immunoglobulin variable and constant region genes belonging to different species. For example, the variable segments of the genes from a mouse monoclonal antibody can be joined to human constant segments, such as kappa and gamma 1 or gamma 3. In one example, a therapeutic chimeric antibody is thus a hybrid protein composed of the variable or antigen-binding domain from a mouse antibody and the constant or effector domain from a human antibody, although other mammalian species can be used, or the variable region can be produced by molecular techniques. Methods of making chimeric antibodies are well known in the art, e.g., see U.S. Patent No.5,807,715. A "humanized" immunoglobulin is an immunoglobulin inc1uding a human framework region and one or more CDRs from a non-human (such as a mouse, rat, or synthetic) immunoglobulin. The non-human immunoglobulin providing the CDRs is termed a "donor" and the human immunoglobulin providing the framework is termed an "acceptor." In one embodiment, all the CDRs are from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not be present, but if they are, they must be substantially identical to human immunoglobulin constant regions, i.e., at least about 85-90%, such as about 95% or more identical. Hence, all parts of a humanized immunoglobulin, except possibly the CDRs, are substantially identical to corresponding parts of natural human immunoglobulin sequences. A "humanized antibody" is an antibody comprising a humanized light chain and a humanized heavy chain immunoglobulin. A humanized antibody binds to the same antigen as the donor antibody that provides the CDR’s. The acceptor framework of a humanized immunoglobulin or antibody may have a limited number of substitutions by amino acids taken from the donor framework. Humanized or other monoc1onal antibodies can have additional conservative amino acid substitutions, which have substantially no effect on antigen binding or other immunoglobulin functions. Exemplary conservative substitutions are those such as gly, ala; val, ile, leu; asp, glu; asn, gln; ser, thr; lys, arg; and phe, tyr. Humanized immunoglobulins can be constructed by means of genetic engineering (e.g., see U.S. Patent No. 5,585,089). A human antibody is an antibody wherein the light and heavy chain genes are of human origin. Human antibodies can be generated using methods known in the art. Human antibodies can be produced by immortalizing a human B cell secreting the antibody of interest. Immortalization can be accomplished, for example, by EBV infection or by fusing a human B cell with a myeloma or hybridoma cell to produce a trioma cell. Human antibodies can also be produced by phage display methods (see, e.g., WO91/17271; WO92/001047; WO92/20791) or selected from a human combinatorial monoclonal antibody library (see the Morphosys website). Human antibodies can also be prepared by using transgenic animals carrying a human immunoglobulin gene (for example, see WO93/12227; WO 91/10741). Humanization of murine antibodies may be conducted according to the following procedure: For humanization of an antibody of murine origin the antibody sequence is analyzed for the structural interaction of framework regions (FR) with the complementary determining regions (CDR) and the antigen. Based on structural modelling an appropriate FR of human origin is selected and the murine CDR sequences are transplanted into the human FR. Variations in the amino acid sequence of the CDRs or FRs may be introduced to regain structural interactions, which were abolished by the species switch for the FR sequences. This recovery of structural interactions may be achieved by random approach using phage display libraries or via directed approach guided by molecular modelling (Almagro and Fransson 2008. Humanization of antibodies. Front Biosci. 13:1619-33). Methods for obtaining monoclonal antibodies In all of the following embodiments, the term monoclonal antibody is meant to include monoclonal antibodies, as well as fragments of monoclonal antibodies, such as the ones detailed herein, more particularly monoclonal antibodies. Hybridoma In a further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by a method comprising: i) fusing antibody-secreting cells from an animal previously immunized with an antigen with myeloma cells to obtain a multitude of hybridomas, ii) isolating from said multitude of hybridomas a hybridoma producing a desired monoclonal antibody. In certain embodiments, the antibody according to the present invention is a monoclonal antibody obtainable by isolating from a multitude of hybridomas a hybridoma producing a desired monoclonal antibody, wherein said multitude of hybridomas were produced by fusing antibody- secreting cells from an animal previously immunized with an antigen with myeloma cells to obtain multitude of hybridomas. A desired monoclonal antibody is in particular a monoclonal antibody binding the antigen, in particular with a binding affinity of at least 107 M-1, preferred 108 M-1, more preferred affinity is greater than 109 M-1, most preferred greater than 1010 M-1. In certain embodiments of the method for obtaining an antibody, in step i) the animal is a mammal, particularly a rabbit, a mouse or a rat, more particularly a mouse, more particularly a Balb/c mouse. In certain embodiments of the method for obtaining an antibody, in step i) the antibody-secreting cell is a splenocyte, more particularly an activated B-cell. In certain embodiments of the method for obtaining an antibody, in step i) fusing involves the use of polyethylene glycol. In certain embodiments of the method for obtaining an antibody, in step i) the myeloma is derived from a mammal, in certain embodiments from the same species of mammal from which the multitude of antibody-secreting cells is obtained. In certain specific embodiments of the method for obtaining an antibody, in step i) the myeloma cells are of the cell line SP2/0. In certain embodiments of the method for obtaining an antibody, said fusing in step i) comprises PEG-assisted fusion, Sendai virus-assisted fusion or electric current-assisted fusion. In certain embodiments of the method for obtaining an antibody, said isolating in step ii) comprises performing an antibody capture assay, an antigen capture assay, and/or a functional screen. In certain embodiments of the method for obtaining an antibody, in step ii) isolating the hybridoma producing a desired monoclonal antibody may involve cloning and re-cloning the hybridomas using the limiting-dilution technique. In one embodiment, said antigen capture assay comprises: a) binding the produced antibodies to a substrate, particularly a solid substrate, b) allowing antigen to bind to said antibodies, c) removing unbound antigen by washing, d) detecting bound antigen; or said antigen capture assay comprises: a) allowing an antigen to bind the produced antibodies to form an antibody-antigen complex, b) binding said antibody-antigen complex to a substrate, particularly a solid substrate, c) removing unbound antigen by washing, d) detecting bound antigen. In one embodiment, said isolating of step ii) comprises performing an enzyme-linked immunosorbent assay, fluorescence-activated cell sorting, cell staining, immunoprecipitation, and/or a western blot. In one embodiment, said detecting of the antibody or the antigen is accomplished with an immunoassay. In one embodiment, the animal is a transgenic animal, in particular a transgenic mouse (wherein in particular the mouse immunoglobulin (Ig) gene loci have been replaced with human loci within the transgenic animal genome), such as HuMabMouse or XenoMouse. In one embodiment, the antigen comprises a peptide as described herein in Table 1, which in certain embodiments (in particular for immunization) may be conjugated to a protein, particularly a serum protein, more particularly a serum albumin, more particularly BSA. In a preferred embodiment, the antibody according to the present invention is a monoclonal antibody obtainable by a method comprising: i) fusing splenocytes cells from a Balb/c mouse previously immunized with a peptide as described herein in Table 1 with SP2/0 myeloma cells using polyethylene glycol, to obtain a multitude of hybridomas, ii) isolating from said multitude of hybridomas a hybridoma producing a desired monoclonal antibody; more preferably, the method comprises: 1) growing hybridomas for a first period (in particular 2 weeks) in HAT medium [RPMI 1640 culture medium supplemented with 20% fetal calf serum and HAT-Supplement] 2) followed replacing HAT medium with HT Medium for a multitude of passages (in particular 3) 3) followed by returning to the normal cell culture medium for a second time period, in particular until the end of three weeks after fusion 4) primary screening of cell culture supernatants for antigen-specific IgG antibodies 5) propagating microcultures of cells that tested positive in 4) 6) retesting cell culture supernatants of microcultures for antigen-specific IgG antibodies 7) cloning and re-cloning cultures that tested positive in 6), using the limiting-dilution technique 8) optionally determining the isotypes of clones obtained from 7) 9) optionally purifying antibodies via Protein A Phage Display In a further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by a method comprising: i) isolating at least one antibody having affinity to an antigen from an antibody gene library; ii) generating at least one cell strain expressing said at least one antibody; iii) isolating the at least one antibody from a culture of the at least one cell strain obtained in step ii). An antibody having affinity to an antigen is in particular an antibody with a binding affinity of at least 107 M-1, preferred 108 M-1, more preferred affinity is greater than 109 M-1, most preferred greater than 1010 M-1. In a certain embodiment, the antibody according to the present invention is a monoclonal antibody obtainable by isolating at least one antibody from a culture derived from at least one cell strain which expressed at least one antibody having affinity to an antigen from an antibody gene library. In one embodiment, the antigen comprises a peptide as described herein in Table 1, which in certain embodiments may be bound to a solid phase. In certain embodiments of the method for obtaining an antibody, in step i) the antibody gene library is a naive antibody gene library, particularly a human naive antibody gene library, more particularly in said library the antibodies are presented via phage display, i.e. on phages comprising a nucleotide sequence encoding for such respective antibody; more particularly the library HAL 7, HAL 8, or HAL 9, more particularly a library comprising the human naive antibody gene libraries HAL7/8. In certain embodiments of the method for obtaining an antibody, in step i) screening comprises the use of an antigen, particularly an antigen containing a tag, more particularly a biotin tag, linked thereto via two different spacers. In particular embodiments, such panning strategy includes a mix of panning rounds with non-specifically bound antigen and antigen bound specifically via the tag, in the case of a biotin tag, bound to streptavidin. In this way, the background of non-specific binders may be minimized. In certain embodiments of the method for obtaining an antibody, in step i), in embodiments wherein the library is a phage display library, the antibody is isolated by isolating a phage presenting said antibody (and comprising a nucleotide sequence encoding for the antibody). In certain embodiments of the method for obtaining an antibody, in step ii) said cell strain is generated via introduction of a nucleotide sequence encoding for the antibody), in embodiments wherein the library in step i) is a phage display library, the isolated phage from step i) may be used to produce a bacterial strain, e.g. an E. coli strain, expressing the antibody. In certain embodiments of the method for obtaining an antibody, in step iv); in embodiments wherein the library in step i) is a phage display library and wherein a bacterial strain is produced in step ii), antibody may be isolated from the supernatant of the culture. It is understood that, as used in describing the methods for obtaining an antibody, the term “one antibody” in the expression “at least one antibody” in particular may include more than one antibody molecule of antibodies having the same amino acid sequence. This understanding applies, mutatis mutandis, to the term “one cell strain”. In certain embodiments of the method for obtaining an antibody, more than one antibody (referring to a multitude of antibodies having distinct amino acid sequences, respectively) is isolated in step i) and accordingly more than one cell strain is generated in step ii). Such method may involve the selection of clones that are positive for binding to the antigen, e.g. via a binding assay, e.g. an ELISA assay involving the antigen, and cells positive for binding to the antigen may be isolated to produce monoclonal cell strains. In a preferred embodiment, the antibody according to the present invention is a monoclonal antibody obtainable by a method comprising: i) isolating at least one antibody having affinity to an antigen from an antibody gene library comprising the human naive antibody gene libraries HAL7/8, by eluting phages carrying said antibody from the library; ii) generating at least one E. coli cell strain expressing said at least one antibody; iii) isolating the at least one antibody from the supernantant a culture of the at least one E. coli cell strain obtained in step ii). In a further aspect, an antibody fragment according to the present invention is produced by a method in volving enzymatic digestion of an antibody. In certain embodiments, this method produces e.g. Fab or F(ab)2 antibody fragments. In certain embodiments, this method involves digestion with pepsin or papain, which are optionally immobilized on a surface. In certain embodiments, antibodies may be humanized by CDR-grafting, in particular by a process involving the steps: - extracting RNA from hybridomas expressing an antibody of interest (e.g. obtained by a method as described herein); - amplifying said extracted RNA via RT-PCR, in particular with primer sets specific for the heavy and light chains of the antibody of interest, to obtain to obtain a DNA product; - further amplifying said DNA product via PCR, in particular using semi-nested primer sets specific for antibody variable regions; - determining the sequence of the DNA product; - aligning said sequence with homologous human framework sequences to determine a humanized sequence for the variable heavy chain and the variable light chain sequences (of the desired antibody). In certain embodiments, antibodies may be humanized by aligning the sequence of a DNA product that was obtained by amplifying RNA extracted from hybridomas expressing an antibody of interest via RT-PCR, in particular with primer sets specific for the heavy and light chains of the antibody of interest and further amplifying the DNA obtained therefrom via PCR, in particular using semi-nested primer sets specific for antibody variable regions, with homologous human framework sequences to determine a humanized sequence for the variable heavy chain and the variable light chain sequences (of the desired antibody). In certain embodiments, antibodies may be humanized by - determining the complementary determining regions (CDR), which may be accomplished by analyzing the structural interaction of framework regions (FR) with the complementary determining regions (CDR) and the antigen; - translplanting said CDR sequences into a human framework region. In certain embodiments, antibodies may be humanized by transplanting CDR sequences, which may preferably have been determined by analyzing the structural interaction of framework regions (FR) with the complementary determining regions (CDR) and the antigen, into a human framework region. In certain embodiments variations in the amino acid sequence of the CDRs or FRs may be introduced to maintain structural interactions with the antigen (which may otherwise be abolished by introducing the human FR sequences), for instance by a random approach using phage display libraries or via directed approach guided by molecular modelling. The DNA sequences encoding for antibodies determined as detailed herein can be transferred by known genetic engineering techniques into cells and used for production of the antibody. Producing antibodies In a further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by the methods described herein, produced by a method comprising: - culturing a cell strain comprising a nucleotide sequence encoding for the antibody; - isolating the antibody from said culture. In a further certain aspect, the antibody according to the present invention is a monoclonal antibody obtainable by the methods described herein, produced by isolating the antibody from a culture of a cell strain comprising a nucleotide sequence encoding for said antibody. In certain embodiments of said method, the cell strain is produced as described herein above and may comprise bacterial cells, such as gram-negative bacteria, e.g. E. coli, Proteus mirabilis, or Pseudomonas putidas, gram-positive bacteria, e.g. Bacillus brevis, Bacillus subtilis, Bacillus megaterium, Lactobacilli such as Lactobacillus zeae/casei or Lactobacillus paracasei, or Streptomyces, such as Streptomyces lividans; eucariotic cells such as yest, e.g. Pichia pastoris, Saccharomyces cerevisiae, Hansenula polymorpha, Schizosaccharomyces pombe, Schwanniomyces occidentalis, Kluyveromyces lactis, or Yarrowia lipolytica; fugi, such as filamentous fungi, e.g. of the genus Trichoderma of Aspergillus, such as A. niger (e.g. subgenus A. awamori) and Aspergillus oryzae, Trichoderma reesei, Chrysosporium, such as C. lucknowense; protozoae, such as Leishmania, e.g. L. tarentolae; insect cells, such as insect cells transfected a Baculovirus, e.g. AcNPV, such as insect cell lines from Spodoptera frugiperda, e.g. Sf-9 or Sf-21, Drosophila melanogaster, e.g. DS2, or Trichopulsia ni, e.g. High Five cells (BTI- TN-5B1-4); mammalian cells such as hamster, e.g. Chinese hamster ovary such as K1-, DukX B11-, DG44, Lec13, or BHK, mouse, e.g. mouse myeloma such as NS0, Homo sapiens, e.g. Per.C6, AGE1.HN, HEK293. In certain embodiments of said method, the cells may be hybridoma cells, e.g. as described herein. In certain embodiments of said method, culturing may take place in a static suspension culture, an agitated suspension culture, a membrane-based culture, a matrix-based culture or a high cell density bioreactor; a vessel for such culturing may be selected from the group comprising a T- flask, a roller culture, a spinner culture, a stirred tank bioreactor, an airlift bioreactor, a static membrane-based or matrix-based culture system, a suspension bioreactor, a fluidized bed bioreactor, a ceramic bioreactor, a perfusion system, a hollow fiber bioreactor. In certain embodiments of said method, the cells may be immobilized on a matrix. A high cell density bioreactor is in particular a culture system capable of generating cell densities greater than 10^8 cells/ml. In a further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by the methods described herein, produced by a method comprising: - generating a transgenic plant or animal comprising a nucleotide sequence encoding for the antibody; - isolating the antibody from said plant or animal or a secretion or product of said plant or animal. In a certain further aspect, the antibody according to the present invention is a monoclonal antibody obtainable by the methods described herein, produced by isolating the antibody from a transgenic plant or transgenic animal or a secretion or product of a transgenic plant or transgenic animal having a nucleotide sequence encoding for the antibody. Said animal may e.g., be selected from a chicken, a mouse, a rat, a rabbit, a cow, a goat, a sheep, a pig; said secretion or product may e.g. be milk or an egg. Said plant may e.g. be selected from tobacco (N. tabacum or N. benthamiana), duckweed (Lemna minor), Chlamydomonas reinhardtii, rice, Arabidopsis thaliana, alfalfa (Medicago sativa), lettuce, maize. The antibodies can in certain embodiments be isolated by physicochemical fractionation, e.g. size exclusion chromatography, precipitation, e.g. using ammonium sulphate, ion exchange chromatography, immobilized metal chelate chromatography gel filtration, zone electrophoresis; based on their classification e.g. binding to bacterial proteins A, G, or L, jacalin; antigen-specific affinity purification via immobilized ligands/antigens; if necessary, low molecular weight components can be removed by methods like dialysis, desalting, and diafiltration. In some embodiments the antibody is encoded by a nucleotide sequence where the nucleotide sequence is a reverse transcription of an amino acid sequence from an antibody produced by one of the processes described herein. With the above context, the following consecutively numbered embodiments provide further specific aspects of the invention: 1. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis and/ or the risk and/ or the severity of reduced graft function, wherein reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. 2. A method for patient stratification and/ or patient selection for early treatment of reduced graft function in a kidney transplantation patient comprising: - determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and - stratifying and/ or selecting said patient for early treatment of reduced graft function in correlation of said level of Pro-Enkephalin or fragments thereof in said sample, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. 3. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 or 2, wherein if said level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient is elevated above a predetermined threshold level, said patient has reduced graft function and/ or is at risk of reduced graft function and/or is stratified and/ or selected for early treatment of reduced graft function. 4. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 3, wherein said predetermined threshold level is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l. 5. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 4, wherein the level of Pro-Enkephalin or fragments thereof is determined in a sample of bodily fluid obtained from said patient (i) at least once before and at least once after or (ii) at least once after kidney transplantation. 6. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 or 2 or 5, wherein samples of bodily fluid are taken from said patient (i) at least once before and at least once after or (ii) at least twice after kidney transplantation and a relative change of the level of Pro-Enkephalin or fragments thereof is calculated, wherein the relative change correlates with the diagnosis and/ or the risk and/ or the severity of reduced graft function of the kidney. 7. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 6, wherein reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient if said relative change between the level of Pro-Enkephalin or fragments thereof in the samples either taken (i) at least once before and at least once after or (ii) at least twice after kidney transplantation is either a decrease of less than 50% or an increase, when the level of the earlier sample is set to 100%. 8. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 7, wherein, (i) if said at least one sample of bodily fluid is taken after kidney transplantation, said sample is obtained within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation. (ii) if said at least two samples of bodily fluids are taken before and after kidney transplantation, said sample of bodily fluid taken after kidney transplantation is obtained, within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation or wherein, (iii) if said at least two samples of bodily fluids are taken after kidney transplantation, said first sample after kidney transplantation is obtained within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 8, wherein said determination of Pro-Enkephalin or fragments thereof is performed as follow-up measurement more than once after kidney transplantation in said patient. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity reduced graft function in a kidney transplantation patient according to embodiments 1 to 9, wherein said patient is in need of renal replacement therapy and/ or administration of a medicament and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs if reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 10, wherein said renal replacement therapy is selected from the group comprising dialysis (hemodialysis or peritoneal dialysis), hemofiltration, and hemodiafiltration. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 10, wherein said administration of a medicament is a treatment with recombinant alkaline phosphatase, pegylated carboxyhemoglobin, relaxin, hepatocyte growth factor, mirocept, C1 esterase inhibitor. 13. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 12, wherein said patient is under immunosuppressive therapy selected from the group comprising interleukin 2 receptor antagonist, calcineurin inhibitors (cyclosporine A, tacrolimus), mammalian target of rapamycin inhibitor, corticosteroids, mycophenolate, sirolimus and azathioprine). 14. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 13, wherein nephrotoxic drugs are selected from the group comprising calcineurin inhibitors for immunosuppression (e.g., cyclosporine A, tacrolimus), pain medications (e.g., Nonsteroidal anti-inflammatory drugs (NSAIDs) as ibuprofen, aspirin), anti-microbials (e.g., aminoglycosides, cephalosporins, penicillins, quinolones, rifampin and vancomycin), cholesterol-lowering statins, angiotensin- converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and diuretics, chemotherapeutic agents (e.g. cisplatin) are changed and/ or reduced and/ or withheld if reduced function is diagnosed and/ or a risk of reduced graft function is predicted in said patient. 15. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 14, wherein said Pro-Enkephalin or fragment is selected from the group comprising SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4, SEQ ID No.5, SEQ ID No.6, SEQ ID No.8, SEQ ID No.9, SEQ ID No.10, SEQ ID No.11 and SEQ ID No.12. 16. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 15, wherein said patient is an adult or child. 17. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 16, wherein said sample of bodily fluid may be selected from the group comprising whole blood, serum, plasma, urine, cerebrospinal liquid (CSF), and saliva. 18. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 17, wherein said sample of bodily fluid may be selected from the group comprising whole blood, blood serum, blood plasma. 19. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 18, wherein additionally at least one clinical parameter is determined selected from the group comprising: alanine aminopeptidase, alkaline phosphatase, gamma-glutamyl transpeptidase, calprotectin, C-C motif chemokine ligand 14, chitinase 3-like protein 1, hepatocyte growth factor, hepcidin, IL-18, beta-trace protein (BTP), cystatin C, KIM-1, TIMP-2, IGFBP-7, blood urea nitrogen (BUN), NGAL, liver-type fatty acid binding protein, monocyte chemoattractant peptide-1, Creatinine Clearance, serum Creatinine (SCr), urea, metrin-1, osteopontin, retinol binding protein, tumor necrosis factor, and Apache Score. 20. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 19, comprising determining the level of Pro- Enkephalin or fragments thereof in a sample of bodily fluid by using at least one binder, wherein said at least one binder binds to a region within the amino acid sequence selected from the group comprising SEQ ID No.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, preferably said at least one binder binds to a region with the sequences selected from the group comprising SEQ ID No.1, 2, 5, 6, 8, 9, 10 and 11, preferably said at least one binder binds to a region with the sequences selected from the group comprising SEQ ID No.1, 2, 5, 6, 8 and 9, preferably said at least one binder binds to SEQ ID No.6. 21. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 20, wherein the level of Pro-Enkephalin or fragments thereof is measured with an immunoassay and said binder is an antibody, or an antibody fragment binding to Pro-Enkephalin or fragments thereof. 22. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 21, wherein an immunoassay is used comprising two binders that bind to two different regions within the region of Pro-Enkephalin that is amino acid 133-140 (LKELLETG, SEQ ID NO. 13) and amino acid 152-159 (SDNEEEVS, SEQ ID No. 14), wherein each of said regions comprises at least 4 or 5 amino acids. 23. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 21 and 22, wherein the assay sensitivity of said assay is < 15 pmol/L, preferably < 10 pmol/L and most preferred < 6 pmol/L. 24. A method for early diagnosis and/ or early prediction of a risk and/ or monitoring of a risk of reduced graft function in a kidney transplantation patient according to embodiments 1 to 23, in order to stratify said patients into risk groups. 25. Method for early treatment of reduced graft function in a kidney transplantation patient, wherein the treatment is selected from the group comprising renal replacement therapy and/ or administration of a medicament and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs, wherein said patient is selected by a diagnostic method comprising the steps: - determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and - correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis of reduced graft function and/ or the risk of reduced graft function, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. 26. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient, wherein said patient is selected by a diagnostic method comprising the steps: - determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and - correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis of reduced graft function and/ or the risk of reduced graft function, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. 27. Medicament for use according to embodiment 26, wherein said medicament is selected from the group comprising recombinant alkaline phosphatase, pegylated carboxyhemoglobin, relaxin, hepatocyte growth factor, mirocept, C1 esterase inhibitor. 28. Use of a point-of-care device for performing a method according to embodiments 1 to 27, wherein said point of care device comprises at least two antibodies or antibody fragments directed to amino acid 133-140 (LKELLETG, SEQ ID No. 13) and amino acid 152-159 (SDNEEEVS, SEQ ID No.14). 29. Use of a kit for performing a method according to embodiments 1 to 27, wherein said kit comprises at least two antibodies or antibody fragments directed to amino acid 133-140 (LKELLETG, SEQ ID No. 13) and amino acid 152-159 (SDNEEEVS, SEQ ID No.14). With the above context, the following embodiments pertaining to an aspect B of the invention also form part of the present invention: 1. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with graft function and/ or the risk and/ or the severity of reduced graft function, wherein reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 1 of aspect B, wherein said method is used for patient stratification and/ or patient selection for early treatment of reduced graft function in a kidney transplantation patient. 3. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 or 2 of aspect B, wherein if said level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient is elevated above a predetermined threshold level, said patient has reduced graft function and/ or is at risk of reduced graft function and/or is stratified and/ or selected for early treatment of reduced graft function. 4. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 3 of aspect B, wherein said predetermined threshold level is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l. 5. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 4 of aspect B, wherein the level of Pro-Enkephalin or fragments thereof is determined in a sample of bodily fluid obtained from said patient (i) at least once before and at least once after or (ii) at least once after kidney transplantation. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 or 2 or 5 of aspect B, wherein samples of bodily fluid are taken from said patient (i) at least once before and at least once after or (ii) at least twice after kidney transplantation and a relative change of the level of Pro- Enkephalin or fragments thereof is calculated, wherein the relative change correlates with graft function and/ or the risk and/ or the severity of reduced graft function of the kidney. 7. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 6 of aspect B, wherein reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient if said relative change between the level of Pro-Enkephalin or fragments thereof in the samples either taken (i) at least once before and at least once after or (ii) at least twice after kidney transplantation is either a decrease of less than 50% or an increase, when the level of the earlier sample is set to 100%. 8. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 7 of aspect B, wherein, (iv) if said at least one sample of bodily fluid is taken after kidney transplantation, said sample is obtained within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation. (v) if said at least two samples of bodily fluids are taken before and after kidney transplantation, said sample of bodily fluid taken after kidney transplantation is obtained, within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation or wherein, (vi) if said at least two samples of bodily fluids are taken after kidney transplantation, said first sample after kidney transplantation is obtained within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation. 9. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 8 of aspect B, wherein said determination of Pro-Enkephalin or fragments thereof is performed as follow-up measurement more than once after kidney transplantation in said patient. 10. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity reduced graft function in a kidney transplantation patient according to embodiments 1 to 9 of aspect B, wherein said patient is in need of renal replacement therapy and/ or administration of a medicament and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs if reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient. 11. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 10 of aspect B, wherein said renal replacement therapy is selected from the group comprising dialysis (hemodialysis or peritoneal dialysis), hemofiltration, and hemodiafiltration. 12. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 10 of aspect B, wherein said administration of a medicament is a treatment with recombinant alkaline phosphatase, pegylated carboxyhemoglobin, relaxin, hepatocyte growth factor, mirocept, C1 esterase inhibitor. 13. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 12 of aspect B, wherein said patient is under immunosuppressive therapy selected from the group comprising interleukin 2 receptor antagonist, calcineurin inhibitors (cyclosporine A, tacrolimus), mammalian target of rapamycin inhibitor, corticosteroids, mycophenolate, sirolimus and azathioprine). 14. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiment 10 of aspect B, wherein nephrotoxic drugs are selected from the group comprising calcineurin inhibitors for immunosuppression (e.g., cyclosporine A, tacrolimus), pain medications (e.g., Nonsteroidal anti-inflammatory drugs (NSAIDs) as ibuprofen, aspirin), anti-microbials (e.g., aminoglycosides, cephalosporins, penicillins, quinolones, rifampin and vancomycin), cholesterol-lowering statins, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and diuretics, chemotherapeutic agents (e.g. cisplatin) and are changed and/ or reduced and/ or withheld if reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient. 15. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 11 of aspect B, wherein said Pro- Enkephalin or fragment is selected from the group comprising SEQ ID No.1, SEQ ID No. 2, SEQ ID No.3, SEQ ID No.4, SEQ ID No. 5, SEQ ID No. 6, SEQ ID No. 8, SEQ ID No.9, SEQ ID No.10, SEQ ID No.11 and SEQ ID No.12. 16. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to embodiments 1 to 12 of aspect B, wherein said sample of bodily fluid may be selected from the group comprising whole blood, serum, plasma, urine, cerebrospinal liquid (CSF), and saliva. 17. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk of reduced graft function in a kidney transplantation patient according to embodiments 1 to 13 of aspect B, wherein said sample of bodily fluid may be selected from the group comprising whole blood, blood serum, blood plasma. 18. Method for early treatment of reduced graft function in a kidney transplantation patient, wherein the treatment is selected from the group comprising renal replacement therapy and/ or administration of a medicament and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs, wherein said patient is selected by a diagnostic method comprising the steps: - determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and - correlating said level of Pro-Enkephalin or fragments thereof in said sample with graft function and/ or the risk of reduced graft function, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. 19. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient, wherein said patient is selected by a diagnostic method comprising the steps: - determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and - correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis of reduced graft function and/ or the risk of reduced graft function, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney. 20. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiment 19 of aspect B, wherein said medicament is selected from the group comprising recombinant alkaline phosphatase, pegylated carboxyhemoglobin, relaxin, hepatocyte growth factor, mirocept, C1 esterase inhibitor. 21. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiments 19 and 20 of aspect B, wherein if said level of Pro- Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient is elevated above a predetermined threshold level, said patient has reduced graft function and/ or is at risk of reduced graft function. 22. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiment 21 of aspect B, wherein said predetermined threshold level is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l. 23. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiments 19 to 22 of aspect B, wherein the level of Pro- Enkephalin or fragments thereof is determined in a sample of bodily fluid obtained from said patient (i) at least once before and at least once after or (ii) at least once after kidney transplantation. 24. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiments 19 to 23 of aspect B, wherein samples of bodily fluid are taken from said patient (i) at least once before and at least once after or (ii) at least twice after kidney transplantation and a relative change of the level of Pro-Enkephalin or fragments thereof is calculated, wherein the relative change correlates with graft function and/ or the risk and/ or the severity of reduced graft function of the kidney. 25. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiment 24 of aspect B, wherein reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient if said relative change between the level of Pro-Enkephalin or fragments thereof in the samples either taken (i) at least once before and at least once after or (ii) at least twice after kidney transplantation is either a decrease of less than 50% or an increase, when the level of the earlier sample is set to 100%. 26. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiments 19 to 25 of aspect B, wherein (i) if said at least one sample of bodily fluid is taken after kidney transplantation, said sample is obtained within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation, or wherein (ii) if said at least two samples of bodily fluids are taken before and after kidney transplantation, said sample of bodily fluid taken after kidney transplantation is obtained, within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation, or wherein (iii) if said at least two samples of bodily fluids are taken after kidney transplantation, said first sample after kidney transplantation is obtained within 96 hours, more preferred within 72 hours, even more preferred within 48 hours, even more preferred within 24 hours, most preferred within 12 hours after kidney transplantation. 27. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiments 19 and 26 of aspect B, wherein said determination of Pro-Enkephalin or fragments thereof is performed as follow-up measurement more than once after kidney transplantation in said patient. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiments 19 to 27 of aspect B, wherein said patient is additionally in need of renal replacement therapy and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs if reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiment 28 of aspect B, wherein said renal replacement therapy is selected from the group comprising dialysis (hemodialysis or peritoneal dialysis), hemofiltration, and hemodiafiltration. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiment 28 of aspect B, wherein nephrotoxic drugs are selected from the group comprising calcineurin inhibitors for immunosuppression (e.g., cyclosporine A, tacrolimus), pain medications (e.g., Nonsteroidal anti-inflammatory drugs (NSAIDs) as ibuprofen, aspirin), anti-microbials (e.g., aminoglycosides, cephalosporins, penicillins, quinolones, rifampin and vancomycin), cholesterol-lowering statins, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and diuretics, chemotherapeutic agents (e.g. cisplatin) and are changed and/ or reduced and/ or withheld if reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiments 19 to 30 of aspect B, wherein said Pro-Enkephalin or fragment is selected from the group comprising SEQ ID No.1, SEQ ID No.2, SEQ ID No. 3, SEQ ID No.4, SEQ ID No.5, SEQ ID No. 6, SEQ ID No. 8, SEQ ID No. 9, SEQ ID No.10, SEQ ID No.11 and SEQ ID No.12. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiments 19 to 31 of aspect B, wherein said sample of bodily fluid may be selected from the group comprising whole blood, serum, plasma, urine, cerebrospinal liquid (CSF), and saliva. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to embodiment 32 of aspect B, wherein said sample of bodily fluid may be selected from the group comprising whole blood, blood serum, blood plasma. 34. Use of a point-of-care device for performing a method according to claims 1 to 16 of aspect B, wherein said point of care device comprises at least two antibodies or antibody fragments directed to amino acid 133-140 (LKELLETG, SEQ ID No.13) and amino acid 152-159 (SDNEEEVS, SEQ ID No.14). 35. Use of a kit for performing a method according to embodiments 1 to 16 of aspect B, wherein said kit comprises at least two antibodies or antibody fragments directed to amino acid 133-140 (LKELLETG, SEQ ID No. 13) and amino acid 152-159 (SDNEEEVS, SEQ ID No.14). 36. A method for prediction of kidney function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the kidney function of said patient, wherein said kidney function is defined as glomerular filtration rate (GFR), creatinine clearance rate (CCr), serum creatinine (SCr), urinalysis, blood urea nitrogen or urine output. 37. The method for prediction of kidney function in a kidney transplantation patient according to embodiment 36 of aspect B, wherein if said level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient is elevated above a predetermined threshold level a reduced kidney function is predicted. 38. The method for prediction of kidney function in a kidney transplantation patient according to embodiments 36 and 37 of aspect B, wherein said prediction is within 12 months, more preferred within 9 months, more preferred within 6 months, more preferred within 3 months, more preferred within 1 month, most preferred within 14 days. 39. The method for prediction of kidney function in a kidney transplantation patient according to embodiment 38 of aspect B, wherein said prediction is a short-term prediction within 3 months, preferably within 1 month, more preferred within 28 days, even more preferred within 21 days, most preferred within 14 days. The method for prediction of kidney function in a kidney transplantation patient according to embodiment 37 of aspect B, wherein said predetermined threshold level is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l. The method for prediction of kidney function in a kidney transplantation patient according to embodiments 36 to 40 of aspect B, wherein the level of Pro-Enkephalin or fragments thereof is determined in a sample of bodily fluid obtained from said patient (i) at least once before and at least once after or (ii) at least once after kidney transplantation. The method for prediction of kidney function in a kidney transplantation patient according to embodiments 36 to 40 of aspect B, wherein samples of bodily fluid are taken from said patient (i) at least once before and at least once after or (ii) at least twice after kidney transplantation and a relative change of the level of Pro-Enkephalin or fragments thereof is calculated, wherein the relative change correlates with said kidney function. The method for prediction of kidney function in a kidney transplantation patient according to embodiment 42 of aspect B, wherein a reduction in kidney function is predicted in said patient if said relative change between the level of Pro-Enkephalin or fragments thereof in the samples either taken (i) at least once before and at least once after or (ii) at least twice after kidney transplantation is either a decrease of less than 50% or an increase, when the level of the earlier sample is set to 100%. The method for prediction of kidney function in a kidney transplantation patient according to embodiments 36 to 43 of aspect B, wherein said Pro-Enkephalin or fragment is selected from the group comprising SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4, SEQ ID No.5, SEQ ID No.6, SEQ ID No.8, SEQ ID No.9, SEQ ID No.10, SEQ ID No. 11 and SEQ ID No.12. The method for prediction of kidney function in a kidney transplantation patient according to embodiments 36 to 44 of aspect B, wherein said sample of bodily fluid may be selected from the group comprising whole blood, serum, plasma, urine, cerebrospinal liquid (CSF), and saliva. 46. The method for prediction of kidney function in a kidney transplantation patient according to embodiments 36 to 44 of aspect B, wherein said sample of bodily fluid may be selected from the group comprising whole blood, blood serum and blood. 47. The method for prediction of kidney function in a kidney transplantation patient according to embodiments 36 to 46 of aspect B, wherein said GFR is estimated GFR (eGFR), true GFR or measured GFR (mGFR). 48. The method for prediction of kidney function in a kidney transplantation patient according to embodiments 36 to 47 of aspect B, wherein a reduction of GFR below 60, preferably below 45, preferably below 30, most preferred below 15 is predicted. EXAMPLES Example 1 Development of Antibodies Peptides Peptides were synthesized (JPT Technologies, Berlin, Germany). Peptides/ conjugates for Immunization: Peptides for immunization (Table 1) were synthesized (JPT Technologies, Berlin, Germany) with an additional N-terminal Cysteine residue for conjugation of the peptides to bovine serum albumin (BSA). The peptides were covalently linked to BSA by using Sulfo-SMCC (Perbio Science, Bonn, Germany). The coupling procedure was performed according to the manual of Perbio. Table 1: immunization peptides and antibody names Peptide for immunization Pro-Enkephalin-sequence Antibody name (C)DAEEDD 119-125 NT-MR-PENK (C)EEDDSLANSSDLLK 121-134 NM-MR-PENK (C)LKELLETG 133-140 MR-MR-PENK (C)TGDNRERSHHQDGSDNE 139-155 MC-MR-PENK (C)SDNEEEVS 152-159 CT-MR-PENK The antibodies were generated according to the following method: A BALB/c mouse was immunized with 100 µg peptide-BSA-conjugate at day 0 and 14 (emulsified in 100 µl complete Freund’s adjuvant) and 50 µg at day 21 and 28 (in 100 µl incomplete Freund’s adjuvant). Three days before the fusion experiment was performed, the animal received 50 µg of the conjugate dissolved in 100 µl saline, given as one intraperitoneal and one intravenous injection. Splenocytes from the immunized mouse and cells of the myeloma cell line SP2/0 were fused with 1 ml 50 % polyethylene glycol for 30 s at 37 °C. After washing, the cells were seeded in 96-well cell culture plates. Hybrid clones were selected by growing in HAT medium [RPMI 1640 culture medium supplemented with 20 % fetal calf serum and HAT-supplement]. After two weeks the HAT medium is replaced with HT Medium for three passages followed by returning to the normal cell culture medium. The cell culture supernatants were primary screened for antigen specific IgG antibodies three weeks after fusion. The positive tested microcultures were transferred into 24-well plates for propagation. After retesting the selected cultures were cloned and re-cloned using the limiting- dilution technique and the isotypes were determined. (Lane, R.D.1985 J. Immunol. Meth.81: 223-228; Ziegler, B. et al.1996. Horm. Metab. Res.28: 11-15). Monoclonal antibody production Antibodies were produced via standard antibody production methods (Marx et al.1997. ATLA 25, 121) and purified via Protein A-chromatography. The antibody purities were > 95 % based on SDS gel electrophoresis analysis. Labelling and coating of antibodies. All antibodies were labelled with acridinium ester according the following procedure: Labelled compound (tracer): 100 µg (100 µl) antibody (1 mg/ml in PBS, pH 7.4), was mixed with 10 µl Acridinium NHS-ester (1 mg/ml in acetonitrile, InVent GmbH, Germany) (EP 0353971) and incubated for 20 min at room temperature. Labelled antibody was purified by gel-filtration HPLC on Bio-Sil SEC 400-5 (Bio-Rad Laboratories, Inc., USA) The purified labelled antibody was diluted in (300 mmol/l potassium phosphate, 100 mmol/l NaCl, 10 mmol/l Na-EDTA, 5 g/l bovine serum albumin, pH 7.0). The final concentration was approx. 800.000 relative light units (RLU) of labelled compound (approx. 20 ng labelled antibody) per 200 µl. Acridiniumester chemiluminescence was measured by using an AutoLumat LB 953 (Berthold Technologies GmbH & Co. KG). Solid phase antibody (coated antibody): Polystyrene tubes (Greiner Bio-One International AG, Austria) were coated (18 h at room temperature) with antibody (1.5 µg antibody/0.3 ml 100 mmol/l NaCl, 50 mmol/l Tris/HCl, pH 7.8). After blocking with 5 % bovine serum albumin, the tubes were washed with PBS, pH 7.4 and vacuum dried. Antibody specificity Antibody cross-reactivities were determined as follows: 1µg peptide in 300 µl PBS, pH 7.4 was pipetted into Polystyrene tubes and incubated for 1h at room temperature. After incubation the tubes were washed 5 times (each 1ml) using 5% BSA in PBS, pH 7.4. Each of the labelled antibodies were added (300 µl in PBS, pH 7.4, 800.000 RLU/ 300 µl) an incubated for 2h at room temperature, After washing 5 times (each 1ml of washing solution (20 mmol/l PBS, pH 7.4, 0.1 % Triton X 100), the remaining luminescence (labelled antibody) was quantified using the AutoLumat Luminometer 953. Synthetic MR-PENK peptide was used as reference substance (100%). The cross-reactivities of the different antibodies are listed in table 2. Table 2: cross-reactivities of the different PENK-antibodies Antibody DAEE EEDDSLAN LKELLE TGDNRERSH SDNEEE MR-PENK DD SSDLLK TG HQDGSDNE VS (SEQ ID NO. 6) NT-MR- 121 10 <1 <1 <1 100 PENK NM-MR- <1 98 <1 <1 <1 100 PENK MR-MR- <1 <1 105 <1 <1 100 PENK MC-MR- <1 <1 <1 115 <1 100 PENK CT-MR- <1 <1 <1 <1 95 100 PENK All antibodies bound the MR-PENK peptide, comparable to the peptides which were used for immunization. Except for NT-MR-PENK-antibody (10% cross reaction with EEDDSLANSSDLLK), no antibody showed a cross reaction with MR-PENK fragments not used for immunization of the individual antibody. Pro-Enkephalin Immunoassay: 50 µl of sample (or calibrator) was pipetted into coated tubes, after adding labelled antibody (200ul), the tubes were incubated for 2 h at 18-25 °C. Unbound tracer was removed by washing 5 times (each 1 ml) with washing solution (20 mmol/l PBS, pH 7.4, 0.1 % Triton X-100). Tube- bound labelled antibody was measured by using the Luminometer 953. Using a fixed concentration of 1000pmol/ of MR-PENK. The signal (RLU at 1000pmol MR-PENK/l) to noise (RLU without MR-PENK) ratio of different antibody combinations is given in table 3. All antibodies were able to generate a sandwich complex with any other antibody. Surprisingly, the strongest signal to noise ratio (best sensitivity) was generated by combining the MR-MR-PENK- and CT-MR-PENK antibody. Subsequently, we used this antibody combination to perform the MR-PENK- immunoassay for further investigations. MR-MR-PENK antibody was used as coated tube antibody and CT-MR-PENK antibody was used as labelled antibody. Table 3: signal to noise ratio of different antibody combinations Solid NT-MR- NM-MR- MR-MR- MC-MR-PENK CT-MR- phase PENK PENK PENK PENK antibody Labelled antibody NT-MR- / 27 212 232 <1 PENK NM-MR- 36 / 451 487 <1 PENK MR-MR- 175 306 / 536 1050 PENK MC-MR- 329 577 542 / <1 PENK CT-MR- <1 615 1117 516 / PENK Calibration: The assay was calibrated, using dilutions of synthetic MR-PENK, diluted in 20 mM K2PO4, 6 mM EDTA, 0.5% BSA, 50 μM Amastatin, 100 μM Leupeptin, pH 8.0. Figure 1 shows a typical Pro- Enkephalin dose / signal curve. The assay sensitivity was 20 determinations of calibrator zero (no addition of MR-PENK) + 2SD) 5.5 pmol/L. Example 2 The aim of this study was to evaluate the capabilities of the biomarker proenkephalin A 119-159 (PENK or penKid) to predict reduced graft function, specifically slow graft function (SGF) and delayed graft function (DGF) of the kidney in kidney transplant patients compared to serum creatinine (SCr). Sample collection and analysis EDTA-plasma samples were obtained from 159 patients. From each patient multiple blood samples were obtained: one sample at the day of transplantation (day 0, prior to transplantation, pre-Tx) and up to 35 days after transplantation (every 24 hours). Plasma samples were measured for SCr with a commercial enzymatic assay. PENK was measured using a double monoclonal sandwich immunoassay as described in Donato et al.2018. (Donato et al.2018. Clin Biochem.58: 72-77). Delayed graft function (DGF) was defined as any renal replacement therapy (RRT) within 7 days post transplantation (n=53). Slow graft function (SGF) was defined as no RRT therapy within 7 days post transplantation and quotient of creatinine on day 7/creatinine on day 0 < 0.7. Immediate graft function (IGF) was defined as no RRT within 7 days post transplantation and quotient of creatinine on day 7/creatinine on day 0 > 0.7. DGF severity was classified into 3 severity groups defined as 0/1 (RRT only on day 0/day 1 =first 24h), 2-7 (RRT ended between day 2 and day 7) and >7 (RRT lasted longer than day 7). All patients were successfully transplanted and recovered kidney function prior to discharge. Statistical analysis Values are expressed as medians and interquartile ranges (IQR), or counts and percentages, as appropriate. Group comparisons of continuous variables were performed using Kruskal-Wallis test, with post-hoc tests for variables with more than two categories. Biomarker data (SCr and PENK) were log-transformed. Categorical data were compared using Pearson's Chi-squared Test for Count Data. Logistic regression was used to evaluate and compare PENK and SCr for their ability to predict DGF. To demonstrate independence from clinical variables, the added value of PENK on top of a multivariable model with the most relevant clinical variables to predict DGF was evaluated based on the likelihood ratio chi-square test for nested models. The concordance index (C index or AUC) is given as an effect measure for uni- and multivariable models. For multivariable models, a bootstrap corrected version of the C index/AUC is given. Receiver- operating-characteristic (ROC) curves were constructed and plotted to assess the sensitivity and specificity of PENK measurements obtained at various time points to predict and diagnose DGF. Change in PENK and SCr was computed as %-level of biomarker concentration prior to transplantation. All statistical tests were 2-tailed and a two-sided p-value of 0.05 was considered for significance. The statistical analyses were performed using R version 4.2.2 (http://www.r-project.org, libraries rms, Hmisc, ROCR) and Statistical Package for the Social Sciences (SPSS) version 22.0 (SPSS Inc., Chicago, Illinois, USA). Results: 159 kidney transplant recipients (of which n=109 were cadavric transplants) were included in the study.53 patients developed DGF. From n=106 non-DGF patients, n=45 developed SGF. Patients who developed DGF were grouped by severity: DGF 0/1 (n=19), DGF 2-7 (n=17) and DGF >7 (n=17). Patient characteristics are depicted in table 4. Table 4: Patient characteristics of the study cohort Variable n all no DGF DGF p-val n=159 n=106 (66.7%) n=53 (33.3%) Age (yrs) - median (IQR) 159 49 [39-60] 47 [36-58] 53 [46-61] < 0.03 Sex, male 159 87 (54.7) 51 (48.1) 36 (67.9) < 0.03 BMI (kgm2 - median (IQR) 159 25 [22.45-29] 23.98 [21.72- 26.8] 26.9 [24.4-30.9] < 0.0001 SBP (mmHg) - median (IQR) 159 140 [130-150] 138 [126.5-150] 141 [130-157] 0.18 DBP (mmHg) - median (IQR) 159 80 [70-90] 80 [70-90] 80 [70-90] 0.52 MAP (mmHg) - median (IQR) 159 98.33 [90-110] 99.33 [90- 109.92] 96.67 [90-110] 0.82 dialysis time preTX (days) - 2369 [811- 17 median (IQR) 152 34 [403.5- 2903 [1821- 3283.25] 3026] 3463] < 0.001 cold ischemia time (hrs) - 159 10 [2.5-14.1 12.67 [9.87- median (IQR) 1] 7.68 [2-13.33] 16.17] < 0.0001 donor age (yrs) - median (IQR) 159 55 [45.5-61.5] 54.5 [45.25-62] 56 [48-61] 0.90 donor SCr (mg/dl) - median (IQR) 132 0.8 [0.68-1] 0.8 [0.68-0.9] 0.85 [0.68-1.33] 0.09 Duration of stay (days) - median (IQR) 159 16 [12-21.5] 13.5 [12-17] 23 [18-31] < 0.0001 living donor (n) - % 159 50 (31.4) 48 (45.3) 2 (3.8) < 0.0001 arterial hypertension (n) - % 159 110 (69.2) 73 (68.9) 37 (69.8) 1.0 Diabetes (n) - % 159 24 (15.1) 13 (12.3) 11 (20.8) 0.13 Adipositas (n) - % 159 36 (22.6) 18 (17) 18 (34) < 0.03 As shown in Fig.2 A, PENK discriminates between patients with DGF and those without (non- DGF, including both, IGF and SGF) as early as 24h post transplantation. After an initial drop in PENK after transplantation, DGF patients remain elevated in PENK until the kidney function for the majority of the group finally sets in (post day 8). The separation between DGF and non-DGF is earlier and more pronounced compared to SCr (Fig.2 B). Patient levels before transplantation (pre-Tx) can differ, as can be seen by the spread of the boxes pre-Tx in Fig. 2 A and B. Hence the change from pre-Tx values was investigated. As shown in Fig.3 A and B, the observed differences between PENK and SCr persist after correcting for pre- Tx concentrations. Fig. 3 A shows that the observed discrimination of PENK between patients with DGF and those without as early as 24h post transplantation is also present if the change from pre-Tx concentration is evaluated. While all patients experience a drop in PENK, most patients with no DGF drop below 50% of pre-Tx concentration within 24h. The comparison to SCr shows that for the majority of non-DGF patients to drop below 50% of pre-Tx concentration takes until day 3. As shown in Fig. 4 A, PENK discriminates between DGF, SGF and IGF as early as 24h post transplantation (day 1, p<0.0001), while SCr does not (Fig.4 B, p=0.0657). Most notably, patients with SGF have significantly lower concentrations of PENK compared to DGF patients as early as day 1 (post-hoc p=0.0002). SCr does not discriminate between SGF and DGF at day 1 (post-hoc p=0.3504). The trajectories until day 21 illustrate that PENK changes precede changes in SCr, throughout the observation period. As shown in Fig. 5 A and B, the observed differences between PENK and SCr persist after correcting for pre-Tx concentrations. A change in PENK discriminates between DGF, SGF and IGF as early as 24h post transplantation (day 1, p<0.0001), so does change in SCr (Fig. 5 B, p<0.0001). Most notably however, patients with SGF have fallen stronger in concentrations of PENK compared to DGF patients as early as day 1 (post-hoc p<0.0001), while SGF and DGF patients cannot be discriminated based on change in SCr, and SGF patients have fallen significantly less than DGF patients at day 1 (post-hoc p=0.0099). The trajectories until day 21 illustrate that PENK changes precede those of SCr, in particular for patients with SGF, throughout the observation period. While PENK can distinguish between SGF (who do not require RRT post transplantation) and DGF (who require RRT post transplantation) as early as 24h post transplantation, both based on absolute concentration and on change from pre-Tx, whereas SCr cannot. This is an important advantage of PENK, as the decision to treat patients developing DGF with RRT and not to treat patients that will develop SGF with RRT can be made much earlier compared to the standard biomarker SCr. In a next step we applied logistic regression for the endpoint DGF vs. SGF (IGF excluded) (Table 5). It confirms the superiority of PENK over SCr at day 1, 2 and 3. PENK is superior to SCr on day 1, 2 and 3 (all p<0.0001). Change in PENK is also superior to change in SCr for change at day 1, 2 and 3 (all p<0.0001). The AUC for PENK increases from 0.73 on day 1 to 0.81 on day 2 and 0.84 on day 3. Notably, change in PENK at day 1 already achieves a similar AUC (0.79), hinting at a gain in time if trajectories from pre-Tx are considered. Table 5: Logistic regression results for endpoint DGF vs. SGF (IGF patients excluded) for PENK, SCr, as well as pre-Tx change of PENK and SCr for the first 3 days post transplantation. Model Chi2: Chi2 statistic; d.f.: degrees of freedom; LR p-value: likelihood ratio p-value; C-Index: concordance index or AUC; CI: confidence interval.

Figure 6 A (absolute) and 6 B (change) illustrate the differences in PENK and SCr for prediction of DGF for day 1, 2 and 3 post transplantation. Exemplary threshold values with the respective sensitivity and specificity are as follows: Using an absolute PENK cut-off at 300 pmol/L at day 1 after transplantation, patients with DGF can be identified with a sensitivity of 95% and specificity of 45% (odds ratio 16.2). Using an absolute PENK cut-off at 200 pmol/L at day 2 after transplantation, patients with DGF can be identified with a sensitivity of 97% and specificity of 40% (odds ratio 22.7). Using an absolute PENK cut-off at 200 pmol/L at day 3 post transplantation, patients with DGF can be identified with a sensitivity of 95% and specificity of 45% (odds ratio 16.2). Using a relative change of PENK of less than 50% from pre-Tx to day 1 post transplantation, patients with DGF can be identified with a sensitivity of 89% and specificity of 41% (odds ratio 5.8). Using a relative change of PENK of less than 50% from pre-Tx to day 2 post transplantation, patients with DGF can be identified with a sensitivity of 71% and specificity of 79% (odds ratio 9.0). Using a relative change of PENK of less than 50% from pre-Tx to day 3 post transplantation, patients with DGF can be identified with a sensitivity of 65% and specificity of 93% (odds ratio 24.0). In a next step we applied logistic regression for the DGF endpoint (Table 6). It confirms the superiority of PENK of SCr at day 1, 2 and 3. PENK is superior to SCr on day 1, 2 and 3 (all p<0.0001) (Fig. 7 A). Change in PENK is also superior to change in SCr for change at day 1, 2 and 3 (all p<0.0001) (Fig.7 B). The AUC for PENK increases from 0.81 on day 1 to 0.88 on day 2 and 0.91 on day 3. Notably, change in PENK at day 1 already achieves a similar AUC (0.87), hinting at a gain in time if trajectories from pre-Tx are considered. Table 7 shows that both, PENK at d1 and change in PENK at d1, provide added value on top of a multivariable model comprising of known clinical risk factors for DGF (both p<0.0001). PENK or change of PENK are in both cases the strongest predictor within the model (both Chi2 >15) and cold ischemia time being the second strongest factor in both models (both Chi2 >5). Table 6: Logistic regression results for endpoint DGF for PENK, SCr, as well as pre-Tx change of PENK and SCr for the first 3 days post transplantation. Model Chi2: Chi2 statistic; d.f.: degrees of freedom; LR p-value: likelihood ratio p-value; C-Index: concordance index or AUC; CI: confidence interval.

Figure 7 A (absolute) and 7 B (change) illustrate the differences in PENK and SCr for prediction of DGF for day 1, 2 and 3 post transplantation. Table 7: Multivariable logistic regression results for endpoint DGF for a model comprising of donor age, donor SCr, living vs. deceased donor, cold ischemia time and patients’ duration on RRT pre-Tx (model ‘Multi’) and said model in combination with PENK at d1 (model ‘Multi, PENK’) or change in PENK at d1 (model ‘Multi, chng PENK’). Model Chi2: Chi2 statistic; d.f.: degrees of freedom; LR p-value: likelihood ratio p-value; C-Index: bootstrap-corrected concordance index or AUC. Fig.8 A and B show that PENK also discriminates between DGF severities earlier than SCr. While SCr in DGF severity 0-1 only fall after two weeks (day 12-15, post-hoc p-value 0.0010), this group declines in PENK already after week 1 (day 6-8, post hoc p-value for PENK <0.0001 and for SCr 0.6113, comparing severity groups 0-1 with >7). Similarly, patients with DGF severity 2-7 decline in PENK in week 2 (day 12-15, post hoc p-value for PENK 0.0374 and for SCr 0.6728, comparing severity groups 2-7 with >7), while only a trend is observed in week 3 for SCr (day 21/last, p=0.1226). This trend is also observed for the change from pre-Tx, see Fig.9 A and B. As an example, using an absolute cut-off for PENK of 300 pmol/L at day 1 after transplantation, patients with DGF can be identified with a sensitivity of 95% and specificity of 57% (odds ratio 25.4). Therefore, 96% of patients with a PENK value below 300 pmol/L at day 1 will develop no DGF (negative predictive value), while 49% of those above 300 pmol/L have or will develop DGF (positive predictive value). As another example, using an absolute cut-off for PENK of 200 pmol/L at day 2 after transplantation, patients with DGF can be identified with a sensitivity of 97% and specificity of 58% (odds ratio 46.2). Therefore, 98% of patients with a PENK value below 200 pmol/L at day 1 will develop no DGF (negative predictive value), while 57% of those above 200 pmol/L have or will develop DGF (positive predictive value). Using a relative change of PENK of less than 50% from pre-Tx to day 1 post transplantation, patients with DGF can be identified with a sensitivity of 89% and specificity of 67% (odds ratio 16.5). Therefore, 58% of patients with less than 50% change pre-Tx PENK concentration at day 1 have or will develop DGF (positive predictive value), while 92% of those with more than 50% change have or will develop no DGF (negative predictive value). Change from pre-Tx to day 2 or 3 provides similar performance criteria. These are cut-off examples and other cut-off values may be used depending on whether it is considered more appropriate to identify most of the patients at risk to develop DGF (or SGF) at the expense of also identifying "false positives", or whether it is considered more appropriate to identify mainly the patients at high risk at the expense of missing several patients at moderate risk. In conclusion, the results demonstrate, that PENK can discriminate patients with delayed graft function from patients with primary graft uptake earlier than SCr. In contrast to SCr, PENK was able to distinguish between DGF and no DGF as early as 24 hours after transplantation measured as single value and compared to a threshold or as a relative change. Moreover, the serial data also strongly suggest that PENK can discriminate between SGF and DGF and can predict duration of DGF (as reflected by DGF severity) much earlier than SCr. Example 3 In a single center observational study proenkephalin A 119-159 (PENK or penKid) was investigated and compared to serum creatinine (SCr) for the prediction of delayed graft function (DGF) at day 7 and reduced estimated glomerular filtration rate (eGFR) at day 30 after kidney transplantation. Sample collection and analysis: Patients above 18 years of age that were scheduled for renal transplantation were included in the study. Exclusion criteria were age below 18 years and pregnancy. Ethylenediaminetetraacetic acid (EDTA) plasma samples were collected at the day of transplantation (0-12 hours prior to transplantation, day 0 or pre-Tx) and up to one day after transplantation (12-24 hours after transplantation, day 1). Serum creatinine measurement was performed via enzymatic methods on an automated chemical analyser (Konelab 20XT, Thermo Fisher Scientific, Waltham, MA, USA). For measurement of PENK a nonautomated immunoluminometric assay as described in Donato et al.2018 was used. (Donato et al.2018. Clin Biochem.58: 72-77). Delayed graft function was defined as requirement of renal replacement therapy (RRT) in the first seven days after transplantation, differentiating DGF severity 0/1 (RRT only on day 0 or day 1, i.e. up to 24 hours after transplantation), DGF severity 2-7 (RRT ended between day 2 and day 7) and DGF severity >7 (RRT lasted longer than day 7). Slow graft function (SGF) was defined as no RRT in the first seven days after transplantation and quotient of SCr on day 7/SCr on day 0 < 0.7. Immediate graft function (IGF) was defined as no RRT in the first seven days after transplantation and quotient of SCr on day 7/SCr on day 0 > 0.7. Reduced eGFR was defined as eGFR <30 ml/min/1.73 m2. The eGFR was determined via the latest CKD-EPI equation (2021). (Inker et al.2021. N Eng J Med.385:1737-1749). Statistical analysis: Medians and interquartile ranges (IQRs) or counts and percentages are reported, as appropriate. The Kruskal-Wallis test was used for group comparisons of continuous variables, with post-hoc tests for variables with more than two categories. Categorical data were compared via Pearson's chi-square test for count data. All statistical tests were 2-tailed and a two-sided p-value of 0.05 was considered for significance. PENK and SCr data were log-transformed and investigated via logistic regression for prediction of DGF. Receiver operating characteristics (ROC) curves were constructed, and the area under the ROC curve (AUC) and the concordance index (C index) were calculated. For all the statistical analyses, R version 4.2.2 (http://www.r-project.org, libraries rms, Hmisc, ROCR) or IBM SPSS Statistics Version 22 (SPSS Inc., Chicago, Illinois, USA) was used. Results: Thirty-eight kidney transplant patients were included in the study. Baseline characteristics are given in Table 5. Fifteen patients (39.5%) developed DGF with severity ranging from DGF 0/1 in two patients to DGF 2-7 in five patients and DGF >7 in eight patients. Of the remaining patients, 13 patients (34.2%) revealed SGF and 10 patients (26.3%) had IGF. Seven patients (18.4%) had a reduced eGFR at day 30 after transplantation. Table 5: Baseline characteristics Variable n all no DGF DGF p-val n=38 n=23 (60.5) n=15 (39.5) Age (years) 38 52.5 [38.5-64] 46 [36-60] 64 [55-68.5] 0.0089 Sex, male 38 12 (31.6) 8 (34.8) 4 (26.7) 0.8657 Body mass index 38 25.9 [20.65- 25.8 [20.9- 26 [18.75-29.2] 0.9405 (kg/m2) 28.85] 28.5] Cold ischemia time 37 7.07 [4.25-10] 5.38 [3.36- 8.92 [7.58- 0.0054 (hours) 7.36] 10.87] Donor age (years) 38 54 [48.25-60] 54 [45.5-60] 55 [51-60] 0,2819 penKid, pre-Tx 32 616.75 [440.18- 622.2 [434.72- 604.85 0.8763 (pmol/L) 899.1] 866.1] [522.32-931.23] 38 437 [220.95- 234.4 [163.6- 573.5 [507.9- <0.0001 penKid, day 1 (pmol/L) 571.35] 361] 709.8] penKid delta day 1/pre- 32 -31.2 [-64.4-- -61.23 [-76.26- -7.02 [-22.43- 0.0005 Tx (% pre-Tx) 4.76] -36.15] 4.94] 32 667.5 [555.75- 717.5 [561.25- 578 [548.5- 0.5593 SCr, pre-Tx (mg/dL) 827] 827] 793] 38 483.5 [394-627] 450 [357.5- 541 [465.5- 0.0620 SCr, day 1 (mg/dL) 541] 707.5] SCr delta day 1/pre-Tx 32 -29.21 [-46.27- -38.95 [-50.02- -5.16 [-39.41- 0.0673 (% pre-Tx) 1.12] -15.8] 10.72] Before transplantation (pre-Tx) biomarker levels (PENK, SCr) did not differ between patients with and without DGF (Figure 10). At 12-24 hours after transplantation (day 1), PENK was significantly increased in patients that developed DGF compared to patients without DGF (no DGF, including both, IGF and SGF) (573.5 [507.9-709.8] pmol/L vs.234.4 [163.6-361] pmol/L, p<0.0001) (Table 2, Figure 10 A). In contrast, the separation of the two groups was not significant for SCr (p=0.062) (Table 5, Figure 10 B). This resulted in a superior C-index of 0.91 (0.81-1) for PENK on day 1 compared to 0.68 (0.51-0.86) for SCr on day 1 for prediction of DGF. Since the patients presented different baseline biomarker levels before transplantation (pre-Tx), the change of biomarker levels from pre-Tx to day 1 (delta) was investigated. Both, PENK and SCr decreased from pre-Tx to day 1 (Table 2). This decrease was less pronounced in the patients with DGF compared to patients without DGF with a significant difference for PENK (-7.02 [- 22.43-4.94] % pre-Tx vs. -61.23 [-76.26--36.15] % pre-Tx, p=0.0005) but not for SCr (Table 2). This resulted in a superior performance of delta PENK compared to delta SCr for prediction of DGF, as displayed in the ROC curves (Figure 11). In the logistic regression analysis, the C-index of delta PENK (0.88 [0.75-1]) was superior to delta SCr (0.7 [0.51-0.88]). The PENK and SCr levels on day 1 were gradually increased in patients with IGF, SGF and DGF (Figure 12). This difference was more pronounced and significant (p<0.0001) for PENK (Figure 12 A), while it was not significant for SCr (p=0.1969) (Figure 12 B). In the post hoc analysis there were significant differences between IGF and DGF (p<0.0001) and between SGF and DGF (p=0.01095) for PENK measured on day 1, i.e. PENK distinguishes between patients that require RRT after transplantation (DGF) and patients that do not require RRT after transplantation (IGF and SGF) as early as 12-24 hours after transplantation allowing timely treatment decisions, while this cannot be achieved by the state-of-the-art biomarker SCr. The DGF severities could be differentiated by PENK on day 1 with gradual decrease in PENK from highest (DGF 0-1) to lowest DGF severity (DGF >7) and no DGF (ANOVA p>0.0001), while there was no significant difference for SCr on day 1 (p=0.10068) (Figure 13). In the post hoc analysis PENK on day 1 was significantly increased in patients with DGF severity >7 (p=0.02167), DGF severity 2-7 (p=0.00993) and borderline significantly increased in patients with DGF severity 0-1 (p=0.07025) compared to patients with no DGF. Regarding the endpoint reduced eGFR at day 30, biomarker levels before transplantation did not differ significantly (Figure 14). However, PENK on day 1 was borderline significantly increased in patients with reduced eGFR at day 30 compared to patients with eGFR >30 ml/min/1.73 m2 at day 30 (p=0.05247). In contrast, SCr did not differentiate between the two groups (p=0.80663). In line with the performance of delta PENK for prediction of DGF, delta PENK was able to predict of reduced eGFR at day 30 (AUC 0.82), while SCr was not useful (AUC 0.55), as displayed in the ROC curves (Figure 15). In the logistic regression analysis, the C-index of delta PENK (0.82 [0.66- 0.99]) was superior to delta SCr (0.54 [0.31-0.79]), as was PENK on day 1 (0.74 [0.59-0.89]) compared to SCr on day 1 (0.53 [0.33-0.74]). In conclusion, the study confirms the results from Example 2 and further demonstrates that PENK can predict delayed graft function, differentiate between SGF and DGF, grade DGF severity and predict reduced eGFR at day 30 as early as 12-24 hours after kidney transplantation, while SCr measured on day 1 after transplantation is not able to identify these high-risk patients. Figure Description Fig.1 - A typical Pro-Enkephalin dose/ signal curve. Fig 2A - Box and Whisker Plot of PENK by DGF at time points prior to transplantation (pre-Tx), on day 1, 2, 3, after one week (day 6-8: day 7, or day 6 or 8 if day 7 was missing), two weeks (day 12-15: day 14, or day 12, 13 or 15 if day 14 was missing) and three weeks (day 21/last: day 21 or last observed prior to discharge). Fig.2B - Box and Whisker Plot of SCr by DGF at time points prior to transplantation (pre-Tx), on day 1, 2, 3, after one week (day 6-8: day 7, or day 6 or 8 if day 7 was missing), two weeks (day 12-15: day 14, or day 12, 13 or 15 if day 14 was missing) and three weeks (day 21/last: day 21 or last observed prior to discharge). ). Cut-off line at 1.2 mg/dL. Fig.3A - Box and Whisker Plot of change of PENK (as percent from pre-Tx) in patients with DGF and non-DGF. Timepoints as defined in figure 2 A and B. Cut-off line at 50% from pre-Tx concentration. Fig.3B – Box and Whisker Plot of change of SCr (as percent from pre-Tx) in patients with DGF and non-DGF. Timepoints as defined in figure 5 A and B. Cut-off line at 50% from pre-Tx concentration. Fig. 4A – Box and Whisker Plot of PENK by DGF, SGF and IGF at time points prior to transplantation (pre-Tx), on day 1, 2, 3, after one week (day 6-8: day 7, or day 6 or 8 if day 7 was missing), two weeks (day 12-15: day 14, or day 12, 13 or 15 if day 14 was missing) and three weeks (day 21/last: day 21 or last observed prior to discharge). Cut-off lines at 80 pmol/L (upper normal value) and 200 pmol/L. Fig.4B - Box and Whisker Plot of SCr by DGF, SGF and IGF at time points prior to transplantation (pre-Tx), on day 1, 2, 3, after one week (day 6-8: day 7, or day 6 or 8 if day 7 was missing), two weeks (day 12-15: day 14, or day 12, 13 or 15 if day 14 was missing) and three weeks (day 21/last: day 21 or last observed prior to discharge). Cut-off line at 1.2 mg/dL. Fig.5A - Box and Whisker Plot of change of PENK (as percent from pre-Tx) in patients with IGF, SGF and DGF. Timepoints as defined in figure 4 A. Cut-off line at 50% from pre-Tx concentration. Fig.5B - Box and Whisker Plot of change of SCr (as percent from pre-Tx) in patients with IGF, SGF and DGF. Timepoints as defined in figure 4 B. Cut-off line at 50% from pre-Tx concentration. Fig. 6A - ROC plot for endpoint DGF vs. SGF (IGF patients excluded), comparing PENK and SCr at day 1, 2 and 3 post transplantation. AUC: area under the receiver operating curve. Fig.6B - ROC plot for endpoint DGF vs. SGF (IGF patients excluded), comparing change from pre-Tx of PENK and SCr at day 1, 2 and 3 post transplantation. AUC: area under the receiver operating curve. Fig. 7A – ROC plot for endpoint DGF, comparing PENK and SCr at day 1, 2 and 3 post transplantation. AUC: area under the receiver operating curve. Fig.7B – ROC plot for endpoint DGF, comparing change from pre-Tx of PENK and SCr at day 1, 2 and 3 post transplantation. AUC: area under the receiver operating curve. Fig.8A – Box and Whisker Plot of PENK by DGF severity at time points prior to transplantation (pre-Tx), on day 1, 2, 3, after one week (day 6-8: day 7, or day 6 or 8 if day 7 was missing), two weeks (day 12-15: day 14, or day 12, 13 or 15 if day 14 was missing) and three weeks (day 21/last: day 21 or last observed prior to discharge). DGF severity groups: no DGF (no RRT post transplantation); 0-1 (RRT only on day 0 or day 1); 2-7 (RRT ended between day 2 and day 7); >7 (RRT lasted longer than day 7). Cut off lines at 80 pmol/L (upper normal value) and 200 pmol/L. Fig. 8B – Box and Whisker Plot of SCr by DGF severity at time points prior to transplantation (pre-Tx), on day 1, 2, 3, after one week (day 6-8: day 7, or day 6 or 8 if day 7 was missing), two weeks (day 12-15: day 14, or day 12, 13 or 15 if day 14 was missing) and three weeks (day 21/last: day 21 or last observed prior to discharge). DGF severity groups: no DGF (no RRT post transplantation); 0-1 (RRT only on day 0 or day 1); 2-7 (RRT ended between day 2 and day 7); >7 (RRT lasted longer than day 7). Cut-off line at 1.2 mg/dL. Fig. 9A – Box and Whisker Plot of change of PENK (as percent from pre-Tx) by DGF severity. Groups and timepoints as defined in figure 7 A and B. Cut-off line at 50% from pre-Tx concentration. Fig. 9B – Box and Whisker Plot of change of SCr (as percent from pre-Tx) by DGF severity. Groups and timepoints as defined in figure 7 A and B. Cut-off line at 50% from pre-Tx concentration. Figure 10 A - Box and whisker plot of proenkephalin A 119-159 (PENK) by delayed graft function (DGF) defined as RRT requirement in the first seven days after transplantation, at time points 0-12 hours before transplantation (pre-Tx) and 12-24 hours after transplantation (day 1). Three grey lines indicate cut-offs at 300 pmol/L, 200 pmol/L (for distinguishing DGF from no DGF) and 89 pmol/L as the upper reference limit for healthy individuals. The x-axis is log- transformed. Figure 10 B - Box and whisker plot of serum creatinine (SCr) by delayed graft function (DGF) defined as RRT requirement in the first seven days after transplantation, at time points 0-12 hours before transplantation (pre-Tx) and 12-24 hours after transplantation (day 1). A grey line indicates an SCr of 2 mg/dL for reference. The x-axis is log-transformed. Figure 11 – Receiver operating characteristic plot for endpoint delayed graft function (DGF) defined as RRT requirement in the first seven days after transplantation, comparing change of proenkephalin A 119-159 (PENK) or serum creatinine (SCr) from 0-12 hours before transplantation to 12-24 hours after transplantation (delta d0/d1). The area under the curve (AUC) is given for PENK and SCr. Figure 12 A – Box and whisker plot of proenkephalin A 119-159 (PENK) by delayed (DGF), slow (SGF) and immediate (IGF) graft function at time points 0-12 hours before transplantation (pre-Tx) and 12-24 hours after transplantation (day 1). DGF defined as RRT in the first seven days after transplantation; SGF defined as no RRT in the first seven days after transplantation and quotient of SCr on day 7/SCr on day 0 < 0.7; IGF defined as no RRT in the first seven days after transplantation and quotient of SCr on day 7/SCr on day 0 > 0.7. Three grey lines indicate cut-offs at 300 pmol/L, 200 pmol/L and 89 pmol/L as the upper reference limit for healthy individuals. The x-axis is log-transformed. Figure 12 B - Box and whisker plot of serum creatinine (SCr) by delayed (DGF), slow (SGF) and immediate (IGF) graft function at time points 0-12 hours before transplantation (pre-Tx) and 12- 24 hours after transplantation (day 1). DGF defined as RRT in the first seven days after transplantation; SGF defined as no RRT in the first seven days after transplantation and quotient of SCr on day 7/SCr on day 0 < 0.7; IGF defined as no RRT in the first seven days after transplantation and quotient of SCr on day 7/SCr on day 0 > 0.7. A grey line indicates an SCr of 2 mg/dL for reference. The x-axis is log-transformed. Figure 13 A – Box and whisker plot of proenkephalin A 119-159 (PENK) by delayed graft function (DGF) severity at time points 0-12 hours before transplantation (pre-Tx) and 12-24 hours after transplantation (day 1). DGF severity groups are as follows: no DGF (no RRT after transplantation); 0-1 (RRT only on day 0 or day 1); 2-7 (RRT ended between day 2 and day 7); >7 (RRT lasted longer than day 7). Three grey lines indicate cut-offs at 300 pmol/L, 200 pmol/L and 89 pmol/L as the upper reference limit for healthy individuals. The x-axis is log-transformed. Figure 13 B – Box and Whisker Plot of serum creatinine (SCr) by delayed graft function (DGF) severity at time points 0-12 hours before transplantation (pre-Tx) and 12-24 hours after transplantation (day 1). DGF severity groups are as follows: no DGF (no RRT after transplantation); 0-1 (RRT only on day 0 or day 1); 2-7 (RRT ended between day 2 and day 7); >7 (RRT lasted longer than day 7). A grey line indicates an SCr of 2 mg/dL for reference. The x-axis is log-transformed. Figure 14 A - Box and whisker plot of proenkephalin A 119-159 (PENK) by reduced estimated glomerular filtration rate (eGFR) at day 30 (defined as eGFR <30 ml/min/1.73 m2) at time points 0-12 hours before transplantation (pre-Tx) and 12-24 hours after transplantation (day 1). Three grey lines indicate cut-offs at 300 pmol/L, 200 pmol/L and 89 pmol/L as the upper reference limit for healthy individuals. The x-axis is log-transformed. Figure 14 B - Box and whisker plot of serum creatinine (SCr) by reduced estimated glomerular filtration rate (eGFR) at day 30 (defined as eGFR <30 ml/min/1.73 m2) at time points 0-12 hours before transplantation (pre-Tx) and 12-24 hours after transplantation (day 1). A grey line indicates an SCr of 2 mg/dL for reference. The x-axis is log-transformed. Figure 15 – Receiver operating characteristic plot for endpoint reduced estimated glomerular filtration rate (eGFR) at day 30 (defined as eGFR <30 ml/min/1.73 m2) comparing change of proenkephalin A 119-159 (PENK) or serum creatinine (SCr) from 0-12 hours before transplantation to 12-24 hours after transplantation (delta d0/d1). The area under the curve (AUC) is given for PENK and SCr.

Claims

CLAIMS 1. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with graft function and/ or the risk and/ or the severity of reduced graft function, wherein reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney.

2. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to claims 1, wherein said method is used for patient stratification and/ or patient selection for early treatment of reduced graft function in a kidney transplantation patient.

3. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to claims 1 or 2, wherein if said level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient is elevated above a predetermined threshold level, said patient has reduced graft function and/ or is at risk of reduced graft function and/or is stratified and/ or selected for early treatment of reduced graft function.

4. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk or prediction of the severity of reduced graft function in a kidney transplantation patient according to claim 3, wherein said predetermined threshold level is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l.

5. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to claims 1 to 4, wherein the level of Pro-Enkephalin or fragments thereof is determined in a sample of bodily fluid obtained from said patient (i) at least once before and at least once after or (ii) at least once after kidney transplantation.

6. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to claims 1 to 5, wherein said determination of Pro- Enkephalin or fragments thereof is performed as follow-up measurement more than once after kidney transplantation in said patient.

7. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity reduced graft function in a kidney transplantation patient according to claims 1 to 6, wherein said patient is in need of renal replacement therapy and/ or administration of a medicament and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs if reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient.

8. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to claim 7, wherein said administration of a medicament is a treatment with recombinant alkaline phosphatase, pegylated carboxyhemoglobin, relaxin, hepatocyte growth factor, mirocept, C1 esterase inhibitor.

9. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to claim 7, wherein nephrotoxic drugs are selected from the group comprising calcineurin inhibitors for immunosuppression (e.g., cyclosporine A, tacrolimus), pain medications (e.g., Nonsteroidal anti-inflammatory drugs (NSAIDs) as ibuprofen, aspirin), anti-microbials (e.g., aminoglycosides, cephalosporins, penicillins, quinolones, rifampin and vancomycin), cholesterol-lowering statins, angiotensin- converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and diuretics, chemotherapeutic agents (e.g. cisplatin) and are changed and/ or reduced and/ or withheld if reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient.

10. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to claims 1 to 7, wherein said Pro-Enkephalin or fragment is selected from the group comprising SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4, SEQ ID No.5, SEQ ID No. 6, SEQ ID No. 8, SEQ ID No.9, SEQ ID No.10, SEQ ID No.11 and SEQ ID No.12.

11. A method for early diagnosis of graft function and/ or early prediction of a risk and/ or monitoring of a risk and/ or prediction of the severity of reduced graft function in a kidney transplantation patient according to claims 1 to 10, wherein said sample of bodily fluid may be selected from the group comprising whole blood, serum, plasma, urine, cerebrospinal liquid (CSF), and saliva.

12. Method for early treatment of reduced graft function in a kidney transplantation patient, wherein the treatment is selected from the group comprising renal replacement therapy and/ or administration of a medicament and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs, wherein said patient is selected by a diagnostic method comprising the steps: - determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and - correlating said level of Pro-Enkephalin or fragments thereof in said sample with graft function and/ or the risk of reduced graft function, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney.

13. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient, wherein said patient is selected by a diagnostic method comprising the steps: - determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient and - correlating said level of Pro-Enkephalin or fragments thereof in said sample with the diagnosis of reduced graft function and/ or the risk of reduced graft function, wherein the reduced graft function is slow graft function (SGF) or delayed graft function (DGF) of the kidney.

14. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to claim 13, wherein said medicament is selected from the group comprising recombinant alkaline phosphatase, pegylated carboxyhemoglobin, relaxin, hepatocyte growth factor, mirocept, C1 esterase inhibitor.

15. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to claim 13 and 14, wherein if said level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient is elevated above a predetermined threshold level, said patient has reduced graft function and/ or is at risk of reduced graft function.

16. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to claim 15, wherein said predetermined threshold level is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l.

17. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to claims 13 to 16, wherein said patient is additionally in need of renal replacement therapy and/ or adjustment of immunosuppressive therapy and/ or adjustment of nephrotoxic drugs if reduced graft function is diagnosed and/ or a risk of reduced graft function is predicted in said patient.

18. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to claims 13 to 17, wherein said Pro-Enkephalin or fragment is selected from the group comprising SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4, SEQ ID No.5, SEQ ID No.6, SEQ ID No.8, SEQ ID No.9, SEQ ID No.10, SEQ ID No. 11 and SEQ ID No.12.

19. Medicament for use in early treatment of reduced graft function in a kidney transplantation patient according to claims 13 to 18, wherein said sample of bodily fluid may be selected from the group comprising whole blood, serum, plasma, urine, cerebrospinal liquid (CSF), and saliva.

20. A method for prediction of kidney function in a kidney transplantation patient comprising: ^ determining the level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient; and ^ correlating said level of Pro-Enkephalin or fragments thereof in said sample with the kidney function of said patient, wherein said kidney function is defined as glomerular filtration rate (GFR), creatinine clearance rate (CCr), serum creatinine (SCr), urinalysis, blood urea nitrogen or urine output.

21. The method for prediction of kidney function in a kidney transplantation patient according to claim 20, wherein if said level of Pro-Enkephalin or fragments thereof in a sample of bodily fluid obtained from said patient is elevated above a predetermined threshold level a reduced kidney function is predicted.

22. The method for prediction of kidney function in a kidney transplantation patient according to claims 20 and 21, wherein said prediction is within 12 months, more preferred within 9 months, more preferred within 6 months, more preferred within 3 months, more preferred within 1 month, most preferred within 14 days.

23. The method for prediction of kidney function in a kidney transplantation patient according to claim 21, wherein said predetermined threshold level is in the range between 50 and 750 pmol/l, more preferred in the range between 100 and 500 pmol/l, even more preferred in the range between 150 and 400 pmol/l, most preferred in the range between 200 and 300 pmol/l.

24. The method for prediction of kidney function in a kidney transplantation patient according to claims 20 to 23, wherein the level of Pro-Enkephalin or fragments thereof is determined in a sample of bodily fluid obtained from said patient (i) at least once before and at least once after or (ii) at least once after kidney transplantation.

25. The method for prediction of kidney function in a kidney transplantation patient according to claims to 24, wherein said Pro-Enkephalin or fragment is selected from the group comprising SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4, SEQ ID No.5, SEQ ID No.6, SEQ ID No.8, SEQ ID No.9, SEQ ID No.10, SEQ ID No.11 and SEQ ID No.12.

26. The method for prediction of kidney function in a kidney transplantation patient according to claims 20 to 25, wherein said sample of bodily fluid may be selected from the group comprising whole blood, serum, plasma, urine, cerebrospinal liquid (CSF), and saliva.

27. The method for prediction of kidney function in a kidney transplantation patient according to claims 20 to 26, wherein said GFR is estimated GFR (eGFR), true GFR or measured GFR (mGFR).

28. The method for prediction of kidney function in a kidney transplantation patient according to claims 20 to 27, wherein a reduction of GFR below 60, preferably below 45, preferably below 30, most preferred below 15 is predicted.