The functional units in the kidneys, 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 (Figure 1). 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 together with the slit diaphragms of the interdigitating foot-process of the podocytes makes up the filtration barrier.

Many diseases affect kidney function by attacking the glomeruli, the units within the kidney where blood is cleaned. Glomerular diseases include many conditions with a variety of genetic and environmental causes, but they fall into two major categories:

  • Glomerulonephritis describes the inflammatory state of the glomerulus.
  • Glomerulosclerosis describes the scarring or hardening of the glomerular blood vessels.

Although glomerulonephritis and glomerulosclerosis have different causes, they can both lead to kidney failure.

Glomerular diseases damage the glomeruli, letting protein and sometimes red blood cells leak into the urine. Sometimes a glomerular disease also interferes with the clearance of waste products by the kidney, causing their build up in the blood. Furthermore, loss of blood proteins like albumin in the urine can result in a fall in their level in the bloodstream causing changes in fluid homeostasis. Fluids can therefore accumulate outside the circulatory system in the face, hands, feet, or ankles and cause swelling. Different types of glomerular disease exist, but the overall categories for glomerular disease are listed in Figure 2.

How many have glomerular disease?
The prevalence of glomerular diseases in the general population is difficult to evaluate as optimal conditions for performing epidemiologic surveys are difficult to find. However, recent studies from Europe and Australia have suggested a change in the pattern of glomerular diseases in the community where focal segmental glomerulosclerosis is increasing in incidence in the black and Hispanic population. Glomerular disease are an important cause of acute kidney injury (AKI) and they account for approximately 15% of end-stage renal disease (ESRD).

How is glomerular disease treated?
As with general CKD, the first step in treating glomerular disease is to control hypertension. In infectious diseases, treatment aims to remove the infectious agent. In autoimmune diseases, immunosuppressive drugs and “blood-cleaning therapy” (plasmapheresis) are utilized to remove autoantibodies. Some patients are treated with corticosteroid therapy (e.g. minimal change disease and lupus nephritis). In patients experiencing swelling due to changes in fluid homeostasis, diuretics are recommended. With good management of hypertension and other underlying disease drivers, kidney dysfunction and other complications can be prevented or delayed. Due to the reservoir of nephrons, patients are usually diagnosed when the disease is already advanced. Patients that reach end-stage kidney disease require dialysis or kidney transplantation. 

What are the symptoms of glomerular disease, and how is it diagnosed?
The signs and symptoms of glomerular disease include

  • albuminuria: large amounts of protein in the urine
  • hematuria: blood in the urine
  • reduced glomerular filtration rate: inefficient filtering of wastes from the blood
  • hypoproteinemia: low blood protein
  • edema: swelling in parts of the body

One or more of these symptoms can be the first sign of kidney disease.

Patients with glomerular disease have significant amounts of protein in the urine, which may be referred to as "nephrotic range" if levels are very high. Red blood cells in the urine are a frequent finding as well, particularly in some forms of glomerular disease. Urinalysis provides information about kidney damage by indicating levels of protein and red blood cells in the urine. Blood tests measure the levels of waste products such as creatinine and urea nitrogen to determine whether the filtering capacity of the kidneys is impaired. If these lab tests indicate kidney damage, the doctor may recommend ultrasound or an x-ray to see whether the shape or size of the kidneys is abnormal. These tests are called renal imaging. But since glomerular disease causes problems at the cellular level, the doctor will probably also recommend a kidney biopsy—a procedure in which a needle is used to extract small pieces of tissue for examination with different types of microscopes, each of which shows a different aspect of the tissue. A biopsy may be helpful in confirming glomerular disease and identifying the cause.

The medical need for glomerular disease is in line with what is required for chronic kidney disease, where the current diagnostic markers lack in sensitivity. Consequently, novel diagnostic biomarkers may be used as complementary tools to identify patients that are likely to have fibrotic alterations in their glomeruli, and generally identify patients with early disease with only mild or no symptoms. There is also an unmet need for prognostic biomarkers, able to identify patients at higher risk of progression to end stage renal disease, and other adverse outcomes. 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 cost. Biomarkers can also aid drug development by monitoring the therapeutic efficacy, if their 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.

As the biopsy procedure is painful, and has potential complications (bleeding, infections etc), tools to non-invasively assess the state of the tissue would aid both clinical decisions, but also select patients with a more active disease (prognostic enrichment for clinical trials), or that may be more likely to respond to therapy (predictive; complementary vs companion diagnostic). The Protein FingerprintTM technology detects epitopes of relevant extracellular matrix proteins that are generated by proteases that are either up- or downregulated in the disease. By combining these two processes it is possible to detect biomarkers of formation and degradation of the protein of interest, and thereby get an understanding of the tissue turnover. These biomarkers can be used as pharmacodynamic targets to assess the impact of the treatment on the extracellular matrix turnover.

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 and the treatment. In glomerular disease the predominant effect is at first seen in the glomerulus. However, after repetitive, or chronic insults, interstitial fibrosis and tubular atrophy develops.

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).

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

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