Nephropathology all

Theme 5: Nephropathology

Introduction

• The kidneys remove waste products from the blood and excrete them via the urine
• The filtering units of the kidneys are the nephrons, consisting of glomeruli and tubules
• Nephrons can be injured by various factors, leading to loss of proteins in the urine, edema, and accumulation of waste products in the blood
• Glomerular injury can progress to glomerulosclerosis and degeneration of the tubular system

Glomerulosclerosis

• Characterized by excessive accumulation of extracellular matrix components and loss of cells via apoptosis
• Can be regarded as a progressive tissue reaction after kidney injury, in which the natural capacity of the renal tissue to repair and remodel its original architecture has been lost
• Main cause of glomerulosclerosis is aging, due to decreased blood flow and oxygen supply
• Can be classified into focal and segmental glomerulosclerosis
  • Focal glomerulosclerosis: <50% of all glomeruli are involved
  • Segmental glomerulosclerosis: majority of involved glomeruli show sclerosis in <50% of cut surface
• Typical for old age: focal global glomerulosclerosis

Causes of Glomerulosclerosis

• Aging
• Ischemia (arteriosclerosis, thickening of blood vessel wall)
• Inflammation (glomerulonephritis, chronic rejection)
• Endocrine (diabetic nephropathy)
• Epithelial damage (genetic, congenital nephrotic syndrome, PKD, minimal change disease/FSGS)
• Infection (HIV, CMV, Hepatitis C)
• Hyperperfusion (nephron loss, cell damage)
• Unknown (primary FSGS)

Anatomy of the Kidney

• Nephrons consist of glomeruli and the Henle mechanisms
• Glomeruli consist of the following structures:
  • Bowman's capsule
  • Capillaries
  • Mesangium
  • Endothelial cells
  • Podocytes
  • Basement membrane

Inflammation as a Cause of Glomerulosclerosis

• Relation between glomerular localization of immune complexes and clinical picture
• Inflammation usually involves the activation of the humoral immune system, resulting in the formation of immune complexes
• Immune complexes can be deposited in different locations, leading to different disease phenotypes
• The location of the immune complex determines the disease phenotype

Nephritic Syndrome

• Hematuria
• Renal dysfunction
• Hypertension
• Treatment: inflammation reducing drugs, steroids, and cytostatics

Glomerular Localization of Immune Complexes

• Subendothelial deposits
  • Usually involve alloantigens (breakdown products of microorganisms) or autoantigens (autoimmune diseases)
  • The result of subendothelial deposits: activation of the complement system, recruitment of granulocytes, and proteases
• Glomeruli basal membrane deposits (anti-GBM nephritis)
  • Autoantibodies against epitopes in the basal membrane
  • Diseases include Alport disease and Goodpasture syndrome
• Subepithelial deposits
  • Usually involve alloantigens or autoantigens
  • Can lead to membranous glomerulopathy and nephrotic syndrome
• Mesangial deposits
  • Usually involve IgA nephropathy or autoantibodies against mesangial antigens
  • Can lead to inflammation and scarring of the mesangium

Treatment

• Anti-inflammatory agents
• Steroids
• Cytostatics
• Plasmapheresis (for circulating free antibodies)
• Protein-free diets

Clinical Nephrology

• Kidney function: production of urine, excretion of wastes, blood pressure regulation, production of erythropoietin, activation of vitamin D, and acid/base regulation
• Kidney failure: volume overload, accumulation of wastes, hypertension, anemia, bone mineral disease, and metabolic acidosis
• Acute renal insufficiency: tubulo-interstitial, glomerular, and nephrotic diseases
• Glomerular diseases: nephritic and nephrotic diseases
• Nephritic diseases: IgAN, TBMN, Alport, vasculitis, and allograft rejection
• Nephrotic diseases: DM-N, FSGS, minimal change, MN, and myeloma kidney

Experimental Pathology

• Diabetic nephropathy: characterized by thickening of the basement membrane, increased filtration, and leakage of proteins in the urine
• Vascular alterations in diabetic nephropathy: loss of fenestrae and glycocalyx, endothelial swelling, abnormal angiogenesis, arteriolar hyalinosis, and rarefaction
• Vascular endothelial growth factor A (VEGF-A): a fundamental regulator of maintaining the microvasculature, produced by podocytes, binds to VEGFR2, and plays an important role in the maintenance of endothelial cells and glycocalyx### Microangiopathy in patients treated with Bevacizumab
• Bevacizumab is an antibody against VEGF, used to treat tumors by blocking angiogenesis and inhibiting tumor growth.
• However, some patients developed proteinuria as a side effect.

Upregulation of VEGF in developing podocytes

• Mice with upregulated VEGF in glomeruli developed more capillaries, but they became sclerotic and led to proteinuria.
• This suggests that too much VEGF can be harmful.

Increase of VEGF in experimental diabetes

• VEGF and its receptor VEGFR-2 were increased in diabetic mice.

Antibodies against VEGF in experimental diabetes

• Treating diabetic mice with antibodies against VEGF decreased proteinuria.

Reduction of VEGF in diabetic nephropathy

• In humans with diabetic nephropathy, VEGF expression was decreased, opposite to the findings in mice.

Model system to study kidney disease

• Animal models can be used to study kidney disease, offering advantages such as fast development of disease, genetic manipulation, and constant environmental conditions.
• However, there are also disadvantages, including scientific, ethical, and legal issues.

Inducing kidney disease in animal models

• Kidney disease can be induced in animal models through various methods, including drug-induced, spontaneous, environmental/food-induced, genetic-induced, or combinations of these methods.
• Streptozotocin can be used to induce diabetes in animal models by targeting beta cells in the pancreas.

VEGF protects the glomerular microvasculature in diabetes

• VEGF expression can be altered in podocytes using a model that activates Cre recombinase with Dox.
• Podocin is exclusively produced in podocytes and can be used to study VEGF expression.

Summary of VEGF in diabetic nephropathy

• In animal models, VEGF is upregulated, and inhibition has a beneficial effect by reducing proteinuria.
• In human diabetic nephropathy, VEGF expression is downregulated, and podocyte-specific VEGF knockdown worsens diabetic nephropathy.

Inhibiting VEGF action

• VEGF action can be inhibited using small tyrosine kinase inhibitors, antibodies against VEGF receptors, or soluble VEGF receptors.
• Soluble Flt-1, a natural VEGF inhibitor, can bind VEGF in the circulation and prevent binding to a receptor.

Soluble Flt-1 and preeclampsia

• Preeclampsia is characterized by high levels of soluble Flt-1, which can bind VEGF and prevent its activity.

Overall summary

• VEGF plays a role in diabetic nephropathy, and anti-VEGF treatment can improve renal dysfunction in animal models.
• The effect of anti-VEGF treatment depends on pharmaceutical intervention, timing, and dose.

Antigens and Glomerulonephritis

• Alloantigens: come from breakdown products of microorganisms, leading to infections and glomerulonephritis
• Autoantigens: associated with autoimmune diseases, such as lupus erythematosus, and glomerulonephritis

Subendothelial Deposits of Antigens

• Result in activation of the complement system, leading to recruitment of inflammatory cells
• First cells to arrive are granulocytes, which degranulate and release proteases
• Proteases destroy immune complexes, but also damage other cells, leading to holes in capillary walls and leakage of blood cells into the urine (hematuria)
• Granulocytes also release growth factors, which drive proliferation and contribute to increased blood pressure

Nephritic Syndrome

• Characterized by hematuria, renal dysfunction, and hypertension
• Treatment involves inflammation-reducing drugs, steroids, and cytostatics

Glomeruli Basal Membrane

• Autoantibodies can target epitopes in the basal membrane, leading to autoimmune disease (e.g. Goodpasture syndrome)
• Alloimmune disease can occur after transplantation, particularly in patients with Alport disease (mutation in collagen 4)

Anti-GBM Nephritis

• Caused by autoantibodies against epitopes in the glomeruli basal membrane
• Can lead to hematuria and inflammation, with slower progression
• Often associated with microscopic hematuria and scarring, leading to decreased renal function and hypertension

Kidney Function and Failure

• Kidney functions include production of urine, excretion of wastes, blood pressure regulation, production of erythropoietin, activation of vitamin D, and acid/base regulation
• Kidney failure can result in volume overload, accumulation of wastes, hypertension, anemia, bone mineral disease, and metabolic acidosis

Acute Renal Insufficiency

• Divided into tubulo-interstitial and glomerular causes
• Glomerular causes include nephritic and nephrotic diseases, such as IgAN, TBMN, Alport, vasculitis, and allograft rejection
• Urine analysis can help diagnose kidney disease, with nephritic diseases leading to red blood cells in the urine and nephrotic diseases leading to protein leakage (foamy appearance)

Glomerulus

• Healthy glomerulus structure includes Bowman's capsule and capillaries
• Nephritic diseases can lead to proliferation of Bowman's capsule and formation of crescents
• IHC can be used for diagnosis, particularly in cases of lupus

This quiz tests your knowledge on various diseases and disorders related to the renal system, including proteinuria, edema, and glomerulosclerosis. Questions cover the causes, symptoms, and effects of these conditions on the body.