Chronic kidney disease (CKD) is caused by a progressive deterioration of kidney function due to loss of functional units in the kidneys. The functional units, termed nephrons, are made up of the glomerulus and the tubules. The main site of filtration is called the glomerulus, which is made up of an arteriole that curls around itself to create a ball-like structure. The glomerulus is held together by the mesangial matrix, while the surface of the endothelial cells of the arteriole is covered by the foot-processes of the podocytes and the specialized glomerular basement membrane (GBM). The GBM and the slit diaphragms of the interdigitating foot-process of the podocytes make up the filtration barrier. After filtration, the filtrate moves into the tubules (proximal tubules, loop of Henle and distal tubules), where various molecules are reabsorbed or secreted into urine; after this process, urine enters the collecting ducts. Throughout life, nephrons are lost due to injuries and aging. While the loss of nephrons is irreversible, humans are born with a large reservoir of nephrons and a large proportion can be lost before symptoms appear. As the kidney is the main site of excretion of waste products, a reduced kidney function will have widespread effects throughout the body. As an example, patients with CKD are at markedly increased risk of cardiovascular events.

How many have CKD?
Large-scale, nationally representative screening programs undertaken in the 2000s in Australia, Norway, and the US showed that more than 10% of the adult population have CKD. In the western world, diabetes is the leading cause of CKD, followed by hypertension. With the increase in lifestyle diseases such as diabetes and hypertension and the increased life-expectancy, CKD is projected to become an increasing problem worldwide. In 2017, there were 697.5 million cases of CKD globally and approximately 1.2 million people died from CKD.

How is CKD treated?
If detected early, it is possible to pharmacologically halt or slow the progression of CKD. However, due to the reservoir of nephrons, patients are usually diagnosed when CKD is already advanced. Patients that reach end-stage kidney disease require dialysis or kidney transplantation. The main classes of treatments for CKD are drugs regulating blood-pressure or treating the underlying disease drivers (e.g. GLP-1 agonists and SGLT2 inhibitors in diabetes, which have a positive effect on kidney health).

How is CKD diagnosed?
Patients are diagnosed with CKD if the concentration of creatinine in blood and/or proteins or albumin in urine is above a certain threshold. Since serum creatinine only rises after the loss of many nephrons and not all patients present with proteinuria or albuminuria, better diagnostic tools are needed to identify patients at risk of developing CKD.

As stated above, the current diagnostic markers of CKD lack in sensitivity, therefore novel diagnostic biomarkers may be used as complementary tools to identify patients at high risk of developing CKD or with early disease, which can be successfully treated to halt disease progression. There is also an unmet need for prognostic biomarkers, able to identify patients at higher risk of progression to end stage renal disease. Patients with an active disease can be selected to enrich clinical trials. A predictive biomarker would identify the patients more likely to respond to therapy. This would have a great impact on drug development by reducing trial length, size, and costs. Biomarkers can also aid drug development by monitoring the therapeutic efficacy, if the concentration in biological fluids is affected by the treatment. While a number of diagnostic and disease activity biomarkers are under evaluation in CKD, their capacity for risk stratification and treatment response prediction is limited.

In the normal extracellular matrix (ECM) of the kidney, ECM proteins are remodeled as part of normal homeostasis – that is, degraded and replaced by newly synthesized proteins. Collagens are the most abundant ECM proteins in the renal stroma. As a result of repetitive or persistent insults, the balance between ECM degradation and formation is disrupted resulting in net collagen formation. The abnormal collagen formation leads to renal fibrosis, which is the main predictor of progression to end-stage renal disease. The Protein FingerprintTM technology allows quantification of protein fragments generated by the ECM turnover directly in serum and/or urine, thereby monitoring the processes of fibrogenesis and fibrolysis.

In the kidneys, the extracellular matrix is distributed in three main compartments: the tubulointerstitial matrix; the glomerular basement membrane (GBM), supporting endothelial cells and the tubular basement membrane, supporting epithelial cells; and the mesangial matrix. Biomarkers describing the altered turnover of these compartments would allow the characterization and quantification of structural changes in the tissue. The ECM in these different compartments is characterized by the presence of different proteins or protein isoforms. Consequently, the measurement of specific formation or degradation fragments would inform on the compartments most affected by the disease or the treatment.

Collagen biomarkers and tissue characterization:

Tubulointerstitial matrix

  • Degradation: reC1M, C3M, C5M, C6M, C6Ma3, C7M
  • Formation: PRO-C1, PRO-C3, PRO-C5, PRO-C6

 Mesangial matrix :

  • Degradation: C4M, C5M
  • Formation: PRO-C4, PRO-C5, PRO-C18

 Glomerular basement membrane:

  • Degradation: C4Ma3, TUM
  • Formation: PRO-C4

 Tubular basement membrane:

  • Degradation: C4M
  • Formation: PRO-C4

Protein FingerprintTM biomarkers measured in serum and urine are either increased or reduced in CKD patients compared to healthy individuals and correlate with biomarkers of kidney function (creatinine, cystatin C, albuminuria) and inflammation (e.g. CRP, IL-6).

Tubulointerstitial matrix degradation quantified by MMP-9 degraded type III collagen (C3M) in urine

Tubulointerstitial matrix formation quantified  by released pro-peptide of type VI collagen containing endotrophin, a known matrikine with potential deleterious functions (PRO-C6) in serum

Sparding et al Nephrology Dialysis Transplantation, 2018 (FP275)

Sparding et al Nephrology Dialysis Transplantation, 2018 (FP274)

Protein FingerprintTM biomarkers measured in serum and urine are associated with CKD severity and correlate to the extent of fibrosis in histopathological specimens.

Urinary fragments reflecting type III collagen degradation (C3M) and formation (PRO-C3) shift with increasingdiseaseseverity.

Protein Fingerprint biomarkers measured at baseline are prognostic of adverse outcomes including CKD progression, cardiovascular events, and mortality.

Prognostic ability of PRO-C6 in patients with type 2 diabetes with microalbuminuria without symptoms of coronaryarterydisease (BNPcure trial). *Hazard ratios (HR) with 95% CI are listed per doubling. PRO-C6 was adjusted for conventional cardiovascular risk factors (age, sex, systolic blood pressure, LDL cholesterol, smoking, HbA1c, plasma creatinine and UAER). Cardiovascular events was defined as a composite of cardiovascular mortality, stroke, ischaemic cardiovascular disease and heart failure. Disease progression was defined as a decline of eGFR of more than 30%.

Protein Fingerprint biomarkers allow pharmacodynamic profiling of novel treatments by measuring protein fragments reflecting degradation and formation directly in a sample.

Early modulation of Protein FingerprintTM biomarkers following treatment of patients with type 2 diabetes with a GLP1 agonist. Pharmacodynamic biomarkers could assist in dose resolution and information on target engagement/mode of action.

Protein Fingerprint biomarkers at baseline can predict response to treatment by PPARγ agonists (reduction in HbA1c)

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