Project: Early Diagnosis and Monitoring of Renal Diseases

KIDNEY project is aimed at the clinical development of a biochemical test for the early diagnosis of chronic and acute renal failure. Acute Kidney Injury (AKI) is common among hospitalized patients. It affects about _x000D_5 % of general hospitalized patients, and about 25-30% of patients in intensive care units. Chronic Kidney Disease (CKD) is frequently associated with a progressive decrease in the glomerular filtration, which may lead to endstage renal disease (ERD). The number of patients with CKD as well as ERD is dramatically increasing worldwide which poses a high financial burden on health care budgets worldwide. It is a major cause of morbidity but interventions now exist which can reduce risk. Consequently there is a high need for biomarkers that detect early stages of kidney injury and could be used for therapy monitoring. _x000D_In this project the various clinical stages of CKD are investigated for serum and urine concentration of a small protein, named Renal CAF (RCAF). CAF is a specific C-terminal degradation product of agrin produced by the protease neurotrypsin. CAF stands for C-terminal Agrin Fragment and is soluble and detectable in serum and urine. There are two major isoforms of CAF known, Renal CAF (RCAF) and Neuronal CAF (NCAF), which differ in the presence or absence of an amino acids insertion (splice variant) in CAF. RCAF and NCAF have different physiological functions and are produced in spatially different parts of the body. The measurement of the neuronal isoform of CAF (NCAF) is currently linked to the diagnosis and therapy monitoring of sarcopenia and is the subject of the DISARCO development project supported by the Eurostars programme. During the validation of a preliminary test for NCAF aimed at the monitoring of sarcopenia it was discovered that other specific degradation products of agrin produced by neurotrypsin can also be found in relation to renal diseases. The project investigation is focused on RCAF production associated to kidney disorders. New RCAF data of 70 end-stage renal disease patients link RCAF to the functioning of kidneys [see Annex]. The NCAF-specific diagnostic test (under development in the DISARCO project) can’t detect RCAF the isoform which increases during kidney and renal failure._x000D_Neurotune's working concept of this proposal is that an increased production of RCAF (corresponding to an increased activity of neurotrypsin on agrin) occurs in renal disease, and probably at an earlier stage than other markers used for observing kidney function. There is a substantial knowledge of agrin`s role in the kidney however the role of RCAF is just emerging. The UZH will lay the scientific foundation for the role of RCAF in kidney disease, linking the rise in RCAF concentration to a specific status in the development of renal disease._x000D_This working concept has been proved in a small clinical study on patients with various kidney diseases in collaboration with TUM-MED. [see Annex]_x000D_However, these preliminary results need confirmation with larger control and patient groups with state of the art inclusion and exclusion criteria using a certified ELISA test specific for RCAF. _x000D_The proposed project, starting from Neurotune's preliminary assay and the project Ps initial clinical studies, will develop:_x000D__x000D_• An ELISA assay for RCAF suitable for clinical use;_x000D_• A clinical validation and preliminary calibration._x000D__x000D_Clinical diagnosis of renal disease is a complex issue:_x000D__x000D_1) There is not yet a really suitable, well accepted specific biomarker for renal disease comparable for example to troponin for ischaemic heart diseases, though there are some candidates;_x000D_2) The currently used test for creatinine is only moderately specific even normal serum creatinine is influenced by several non-renal factors such as age, gender, muscle mass, muscle metabolism, medications, hydration and nutrition status, and tubular secretion; _x000D_3) A number of acute and chronic kidney conditions can exist with no increase in serum creatinine due to the concept of renal reserve – it is estimated that greater than 50% of kidney function must be lost before serum creatinine rises;_x000D_4) Serum creatinine concentrations do not reflect the true decrease in glomerular filtration rate (GFR) in the acute setting, as several hours to days must elapse before a new equilibrium between the presumably steady state production and the decreased excretion of creatinine is established;_x000D_5) An increase in serum creatinine represents a late indication of a functional change in GFR, which lags behind important structural changes that occur in the kidney during the early damage stage of AKI. _x000D__x000D_High concentrations of RCAF in serum of patients with renal disease and their decrease in patients with successful therapy are observed. The consortium is confident that the ELISA RCAF test could fill the gap and become an important tool for reliable diagnosis and therapy monitoring of renal diseases. _x000D_

Acronym	KIDNEY (Reference Number: 6038)
Duration	01/03/2011 - 28/02/2013
Project Topic	KIDNEY focuses on the validation of a new and most effective diagnostic biomarker (RCAF) for renal disorders including chronic kidney disease (CKD), prognosis of kidney transplants and possibly Acute Kidney Injury (AKI)._x000D_ An ELISA IVD will be developed and validated by means of clinical studies.
Project Results (after finalisation)	We could establish CAF as a new renal boiomarker which potentially helps nephrologists to decide about initiating renal replace treatment therapy after transplantation. Furthermore CAF seems promising in predicting and following diabetic nephropathy.
Network	Eurostars
Call	Eurostars Cut-Off 5

Project partner

Number	Name	Role	Country
4	Klinikum rechts der Isar der Technischen Universität München	Partner	Germany
4	MicroCoat Biotechnologie GmbH	Partner	Germany
4	NEUROTUNE AG	Coordinator	Switzerland
4	University of Zurich - Institute of Physiology	Partner	Switzerland