The functional units in the kidneys, called nephrons, consist of the glomerulus and tubules. The main site of filtration is called the glomerulus. It consists of an arteriole that winds around itself to form a spherical 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 podocytes and the specialized glomerular basement membrane (GBM). The GBM, together with the slit membranes of the interlocking foot processes of podocytes, forms the filtration barrier.
Many diseases affect kidney function by attacking the glomeruli, the units within the kidney where blood is cleansed. Glomerular diseases include many conditions with a variety of genetic and environmental causes, but they fall into two main categories:
Although glomerulonephritis and glomerulosclerosis have different causes, they can both lead to kidney failure. Glomerular disease damages the glomeruli, causing protein and sometimes red blood cells to leak into the urine. Sometimes glomerular disease also impairs the kidney's elimination of waste products, causing them to accumulate in the blood.
In addition, the loss of blood proteins such as albumin in the urine can lead to a decrease in their level in the circulation, resulting in changes in fluid homeostasis. Fluid may therefore accumulate outside the circulatory system in the face, hands, feet, or ankles, causing swelling. There are several types of glomerular disease, but the general categories for glomerular disease are listed in Figure 2.
How many have people glomerular disease?
The prevalence of glomerular disease in the general population is difficult to assess because optimal conditions for conducting epidemiologic surveys are elusive. However, recent studies from Europe and Australia suggest that the pattern of glomerular disease in the general population has changed, and focal segmental glomerulosclerosis is becoming more common in black and Hispanic populations. Glomerular disease is an important cause of acute kidney injury (AKI) and accounts 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. For infectious diseases, treatment is aimed at eliminating the infectious agent. For autoimmune diseases, immunosuppressive drugs and "blood purification therapy" (plasmapheresis) are used to remove autoantibodies. Some patients are treated with corticosteroid therapy (e.g., minimal change disease and lupus nephritis). Diuretics are recommended for patients who have swelling due to changes in fluid homeostasis. With good management of hypertension and other underlying disease factors, renal dysfunction and other complications can be prevented or delayed. Because of the reservoir of nephrons, patients are usually not diagnosed until the disease has progressed. Patients who reach end-stage renal disease require dialysis or kidney transplantation.
What are the symptoms of glomerular disease and how is it diagnosed?
Signs and symptoms of glomerular disease include:
One or more of these symptoms may be the first sign of kidney disease.
Patients with glomerular disease have significant amounts of protein in their urine, which can be referred to as a "nephrotic area" if the levels are very high. Red blood cells in the urine are also a common finding, especially in some forms of glomerular disease.
Urinalysis provides information about kidney damage by showing the levels of proteins and red blood cells in the urine. Blood tests measure levels of waste products such as creatinine and urea nitrogen to determine if the kidneys' filtering capacity is impaired. If these lab tests indicate kidney damage, the doctor may recommend an ultrasound or X-ray to see if the shape or size of the kidneys is abnormal. These tests are called renal imaging.
However, because glomerular disease causes problems at the cellular level, the doctor is also likely to recommend a kidney biopsy - a procedure in which small pieces of tissue are removed with a needle and examined with different microscopes, each showing a different aspect of the tissue. A biopsy can be helpful in confirming glomerular disease and identifying the cause.
The medical need for glomerular disease is similar to that for chronic kidney disease, where current biomarkers are not very sensitive. Consequently, novel exploratory biomarkers can be used as complementary tools to identify patients who are likely to have fibrotic changes in their glomeruli and, more generally, to identify patients with early disease with only mild or no symptoms. There is also an unmet need for prognostic biomarkers capable of identifying patients who are at higher risk of end-stage renal disease or experiencing other adverse outcomes. Patients with active disease can be selected to enrich clinical trials.
A predictive biomarker would identify patients most likely to respond to therapy. This would have a major impact on drug development by reducing the duration, size, and cost of trials. Biomarkers can also aid drug development by monitoring therapeutic efficacy when their concentration in biological fluids is affected by treatment. A number of diagnostic biomarkers and biomarkers of disease activity are currently being studied in CKD, but their ability to stratify risk and predict response to treatment is limited.
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Because biopsy is painful and involves potential complications (bleeding, infection, etc.), tools for noninvasive assessment of tissue status would not only facilitate clinical decisions, but also the selection of patients with more active disease (enrichment for clinical trials) or with a higher likelihood of responding to therapy.
The Nordic ProteinFingerPrint Technology™ detects epitopes of relevant extracellular matrix proteins produced by proteases that are either up- or down-regulated in disease. By combining these two processes, it is possible to detect biomarkers for the formation and degradation of the protein of interest, providing an understanding of tissue turnover. These biomarkers can be used as pharmacodynamic targets to evaluate the effects of treatment on extracellular matrix turnover.
In the kidneys, the extracellular matrix is distributed among 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 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, measurement of specific formation or degradation products would provide information on which compartments are most affected by disease and treatment. In glomerular disease, the predominant effect is initially seen in the glomerulus. However, after repeated or chronic impairment, interstitial fibrosis and tubular atrophy occur.
Collagen biomarkers and tissue characterization:
Tubulointerstitial matrix:
Mesangial matrix:
Glomerular basement membrane :
Tubular basement membrane :
Nordic ProteinFingerPrint Technology™ biomarkers measured in serum and urine are either elevated or decreased in CKD patients compared with healthy individuals and correlate with biomarkers of renal function (creatinine, cystatin C, albuminuria) and inflammation (e.g., CRP, IL-6).
Sparding et al Nephrology Dialysis Transplantation, 2018 (FP275)
Sparding et al Nephrology Dialysis Transplantation, 2018 (FP274)
Nordic ProteinFingerPrint Technology™ biomarkers measured in serum and urine are associated with disease severity and correlate with the extent of fibrosis in histopathologic specimens from patients with IgAN.
Correlations between baseline biomarker concentrations and histological scoring.
Sparding et al Nephrology Dialysis Transplantation, 2018 (FP275)
Sparding et al Nephrology Dialysis Transplantation, 2018 (FP274)
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