Renal System PDF - Cellular and Systemic Pathology

🧪 Renal System Module Cellular and Systematic Pathology Date @October 3, 2024 Lecturer Dr. Les Wood Week Week 2-3 Renal disease is a wide umbrella term for the following: Glome...

🧪 Renal System Module Cellular and Systematic Pathology Date @October 3, 2024 Lecturer Dr. Les Wood Week Week 2-3 Renal disease is a wide umbrella term for the following: Glomerular diseases Glomerulonephritis Nephrotic syndrome Nephritic syndrome Tubulointerstitial diseases Acute tubular necrosis (ATN) Interstitial nephritis Renal vascular diseases Hypertensive nephrosclerosis Renal vascular occlusion (impaired renal blood flow) Cystic disease Polycystic kidney disease Renal cysts Renal System 1  Recap of renal physiology Changes in normal renal function In general, there are 4 major changes in normal renal function which accompany renal disease: Impairment of blood flow through the kidneys, due to a problem with the blood supply. Uraemia, this is an accumulation of waste product urea within the body. Nephrotic syndrome (appearance of protein in urine). Nephritic syndrome (appearance of RBCs in urine) Renal System 2  All of the above may be seen as features of acute and chronic renal failure. Glomerulus The blood supply comes in via the afferent arteriole, circulates round the capillaries and fluid accumulates inside the Bowmans capsule. Blood leaves via the efferent arteriole. This is an image of a normal glomerulus and kidney tubules; we can see it contains both podocytes and mesangial cells. Renal System 3  Above is a lower electron micrograph of the renal glomerulus. CL = capillary lumen. EP = visceral epithelial cells with foot processes. END = endothelium. MES = mesangium. Renal System 4  The image above shows a slice of the glomerulus. Filter comes from the capillaries into the urinary space. The filters have fenestrations, basement membrane and the foot processes forming filtration slits. So to get fluid from capillary into urinary space you need to go through fenestrations, basement membrane and the foot process (podocytes). Renal System 5  PODOCYTES Podocytes are visceral epithelial cells; they are lining cell which form the inner wall of Bowman’s capsule. The cells wrap around the capillary blood vessels of the glomerulus and carry out a function called the foot process in which they form ‘slits’ that blood is filtered through (these are called filtration slits). Renal System 6  The podocytes foot processes projects itself from the podocyte and wraps itself around the capillary, each podocyte interlinks in a way forming small gaps between the foot like pedicle processes. The small gaps are the actual filtration slits, little things could fit through the slits in the podocytes formed round the capillaries but it will be a process of ultrafiltration on a very very small scale. MESANGIAL CELLS Mesangial cells are specialised smooth muscle cells that regulate blood flow through the glomerular capillaries Disruptions of glomerular filtration Renal System 7  CIRCULATING IMMUNE COMPLEX DEPOSITION: Antigen antibody complexes within our circulation get pushed through the blood capillaries and accumulate under the endothelial lining of the capillaries, this is a sub-endothelial deposit disrupting the glomerular wall. ANTI-GLOMERULAR BASEMENT MEMBRANE (anti-gbm): We can have circulating antibodies with no antigen attached, which are antibodies to proteins within the basement membrane, they get through the capillaries and interact with the basement membrane, disrupting it and in turn disrupting the filtration. HEYMAN – an experimental model so do not need to learn. Renal System 8  Immunofluorescence staining is a good way to look at the different patterns within glomerular nephritis In the image above we can see a smoother staining pattern, sometimes known as good Pasteur syndrome. Renal System 9  1. Accumulation of ag-ab complexes underneath the foot processes 2. Deposits are in between the foot processes clogging up the filtration slits. 3. Deposits underneath the endothelium 4. Deposits in and around the mesangial cells Renal System 10  Glomerulonephritis (GN) This is inflammation of the kidney involving the glomeruli. Most types of GN are caused by injury due to the antigen-antibody complexes which are deposited in the walls of the glomerular capillaries and basement membrane (termed immune complex GN). There is a resultant increase in glomerular capillary permeability. ~ LONGER DURATION EFFECTS ~ If the conditions remain untreated, we end up with longer duration effects from further and probably more serious damage. If acute inflammation consists and is long lasting irreversible fibrosis can start to develop around the glomerular walls Renal System 11  forming glomerular sclerosis and scarring of the glomerular tissue, and also tubulointerstitial fibrosis which affects the renal tubules Anything blue in the above image is collagen, as Masson trichrome stain stains collagen blue. We can see all bar one glomerulus are completely clogged up with collagen due to the scarring of the glomerulus tissue from chronic glomerulonephritis. GN may also arise as a result of allergic reactions to toxins which are released by streptococci bacteria. Therefore, seemingly unrelated infections in other organs (e.g. sore throat) may cause kidney damage. The changes to the glomeruli may become permanent which can therefore lead to acute or chronic renal failure. Symptoms of GN include: Proteinuria Haematuria (i.e. nephrotic and nephritic syndrome) Renal System 12  Impairment of blood supply: An impairment of the blood supply is called ischaemia. This can contribute to pre-renal abcute renal failure. I.e. this is something which occurs out with the kidneys affecting renal blood supply. Examples: A reduced circulating volume due to: acute haemorrhage plasma loss (e.g. burns, crush injuries) losses via GI tract (vomiting, diarrhoea) urinary loss All of the above result in hypotension. Renal System 13  Septic shock: The result of all of these changes is a marked reduction in glomerular filtration rate (GFR), and therefore, impaired renal function. A retention of the substances which are normally excreted leads to uraemia. The outcomes of this are: Pre-renal failure which can be reversible resulting in a re-established circulating volume or can be irreversible resulting in intra-renal failure. Renal System 14  Intra renal failure results in damage to kidney cells, the most common cause of this is acute tubular necrosis which can be due to several factors including impaired blood supply and toxic chemicals. What occurs if we have a decreased glomerular filtration rate: Renal System 15 Renal System 16  As necrotic cells breakdown they become necrotic cell debris which accumulates blocking the filtrate from passing through the nephron, which causes the fluid to leak out across the basement membrane and accumulating within the interstitial spaces surrounding the nephrons surrounding the tubule. Damage to the tubular cells can be caused by: Ischaemia Antibiotics (e.g. streptomycin) Heavy metals (Au, Pt, Hg) Radiocontrast agents Endogenous toxin (e.g. myoglobin, antibody light chains) Exposure to toxic chemicals e.g. phenols, CCl4. ATN (acute tubular necrosis) mainly affects: 1. The proximal convoluted tubule, specifically Na+ and HCO3- reabsorption. 2. The Loop of Henle, specifically urine concentrating ability. 3. There will be a very low apparent GFR (140/90 mmHg); glomerulosclerosis and mesangial expansion 3. GFR decreasing (reduced glomerular surface area); macroalbuminuria and overt proteinuria; worsening hypertension; further glomerulosclerosis and loss of podocytes & foot processes (leading to increased UAE); nephron loss due to tubulointerstitial fibrosis. 4. advanced nephropathy and nephrotic proteinuria (>3.5g/day); further declining GFR; worsening hypertension 5. progressive renal failure leading to end-stage renal disease; GFR reduced to 15 ml/min or lower (22L/day); many patients, especially those with type 2 diabetes, never reach ESRD because of the severely increased risk of cardiovascular mortality in this population. Renal System 21 Renal System 22  Post renal failure This occurs ‘downstream’ from the kidneys and is the most common obstruction of the urinary tract due to: calculi carcinomas and tumours congenital defects myeloma myoglobin blood clots following surgery Renal System 23 Renal System 24 Renal System 25 Renal System 26 Renal System 27  Lack of bladder control due to brain, spinal cord or nerve damage. Renal failure implications Renal failure has implications for normal electrolyte imbalance: Renal System 28  Outcomes: Acute renal failure can possibly lead to chronic renal failure which inevitably leads to end-stage renal failure which results in renal replacement therapy (dialysis, renal transplant) Chronic renal failure The primary cause of chronic renal failure causes some nephrons to damage and cease to function, this means that the remaining nephrons have to work harder and increase in size, which increases the individual GFR (dilation of afferent arteriole, increase glomerular hydrostatic pressure). The remaining nephrons become further damaged by an increased blood flow and pressure which results in uraemia. CFR develops in 3 stages: 1. Diminished renal reserve a. Nephrons gradually destroyed until ~75% are lost b. The subject may not show symptoms since remaining nephrons enlarge and compensate for the loss c. If >75% of the nephrons are lost, the subject loses balance between GFR and reabsorption. 2. Renal insufficiency a. There is a greater drop in GFR and an increased blood N-wastes. b. Kidneys cannot effectively concentrate or dilute the urine. Renal System 29  3. End stage renal failure a. ~90% of nephrons are destroyed b. GFR drops to ~10% of normal rate c. Plasma N-wastes are further increased to toxic levels d. Low GFR leads to oliguria. Systemic effects of chronic renal failure: Chronic kidney disease outcomes: dialysis and renal replacement Renal System 30 Renal System 31 Renal System 32