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See Jayraj's notes

Case 1: diabetic nephropathy

  • Creatinine and urea are elevated, indication of GFR, could be something wrong with his kidneys
  • Hypertensive and significant proteinuria
  • Anatomy
    • Podocytes have foor processes that contribute to the basement membrane
    • Nephrin is made by the podocytes and is extracellular, contribute to slit diaphragm and filtration process
      • Congentinal diseases where children lose protein in their urine may be related to nephrin
  • Diabetic microangiopathy: leaking through the glomeruli (capillaries) - proteinuria
    • Thicker walled blood vessels - makes them more leaky
    • Nephrotic syndrome: >3.5 grams of protein. Clinical features - hypoalbuminaemia, oedema (due to less colloid osmotic pressure, lymphatics can't drain away the huge excess), high cholesterol (hepatocytes revved up to replace albumin, then start making more apolipoprotein), massive proteinuria.
      • High cholesterol associated with nephrotic syndrome --> accelerated atherosclerosis (on top of the diabetes risk)
      • Losing immunoglobulins & complement proteins in the urine --> higher infective risk
      • High thrombotic risk --> lose more of anticoagulants (though can occur the other way)

Slide 1

  • Glomeruli are most affected; all of them are at different stages
  • Protein deposition = sclerosis; hyaline appearance
    • Diabetic nodular glomerulosclerosis
  • Arteriolosclerosis: Typically affecting the afferent and efferent
    • hyaline arterolosclerosis
  • End-stage glomerulus isn't losing much protein at all (no blood supply into the glomerulus; no capillaries etc). The associated afferent arteriole has a very thick wall and virtually no lumen. The main protein loss occurs in intermediate stage
    • The tubules are gradually undergoing atrophy and being replaced by connective tissue
    • Proteinuria therefore increases to and intermediate stage, then goes down as all glomeruli become scars --> chronic kidney disease --> need dialysis (low GFR)
  • Tubules are filled with neutrophils in this case -- superimposed acute pyelonephritis
  • Pathogenesis of diabetic nephropathy: advanced glycation endproducts -- crosslinks proteins, makes them less easy to degrade
    • Basement membrane collagen IV doesn't degrade --> thickened
    • Thickened walls also trap LDL more easily --> partly explains accelerated atherosclerosis
    • Proteoglycans and glycosaminoglycans e.g. heparan sulfate in the basement membrane don't stay around.
    • So the basement membrane is thicker but doesn't have as much proteoglycan, which is an important charge barrier (negative), so protein can leak through the membrane
  • Less nephrin molecules in diabetic nephropathy; filtration apparatus is not as effective
  • Eventually all arterioles are blocked and glomeruli becomes scar tissue
  • In adults, the main cause of nephrotic syndrome is membranous nephropathy (e.g. damage to foot processes)

Case 2

  • Causes
    • Pre-renal: anticoagulants (heparin), haemophilia
    • Most likely
      • Tumours - renal cell carcinoma, transitional cell carcinoma
      • Renal calculi - urolithiasis: stones in the renal tract causing irritation - also causes pain when they impact in the renal tract
      • Trauma
      • Renal infarct
    • Others
      • Glomerulonephritis (immune complexes deposited in glomeruli, set off complement cascade. IgA nephropathy commonly produces haematuria without anything else)
      • UTI
      • Urinary tract TB
      • Analgesic nephropathy - rare, but used to be common
        • Compound analgesics that contained both aspirin and paractemol
          • Aspirin decrease renal blood flow due to reduced production of prostacyclins
          • Paracetamol metabolites cause vascular renal injury
          • Bex - aspirin & paracetamol (produces free radicals), caffeine (interferes with blood supply) combined - necrosis intrarenally
        • Ibuprofen can cause salt retention
  • Tests
    • FBC - look at WCC, normal. They have an eryhrocytosis
    • Urine dipstick of MSU - look for rbcs, white cells, nitrates, glucose.
      • MCS - microscopy, culture, sensitivity; casts (of the tubule - indicates problem intrarenally)
      • Red cell casts with dysmorphic red cells - disease in the glomeruli
    • Ultrasounds - cysts, calculi, masses/tumour
    • Intravenous pylography
      • Largely superceded by ultrasound
    • Electrolytes, urea, creatinine
    • Cystoscopy and biopsy (lower urinary tract tumours) - but the
  • FBC
    • Erythrocytosis with no haematuria, proteinuria - concerned it's a tumour (EPO-producing tumour)
    • CT shows huge mass as the left kidney - large, mottled, heterogenous. Left kidney doesn't take up contrast because of necrosis/crumbley, haemorrhage/brown,
      • This is a renal cell carcinoma
    • causes loin pain through stretching the capsule and invasion of surrounding structures
    • blood in urine from the haemorrhage
    • produces EPO --> erythrocytosis (paraneoplastic)
      • NB: CKD people need EPO supplements
  • In fact it's an adenocarcinoma - trying to form glands/tubules
    • This is a moderately-differentiated adenocarcinoma; not very pleomorphic (i.e. there isn't much variation in the size of the cells). Clear-cell variant of renal cell carcinoma - the cells are clear; lipid+glycogen has been washed out. Lipid + glycogen + EPO are being made because the cancer cells are turning on genes that aren't meant to be turned on.
    • Haemosiderin macrophages are eating the red cells
  • Metastases
    • Local lymph nodes, liver, lungs, bone, brain
    • Local invasion - e.g. has it gone through capsule, can grow up to the heart through the IVC
    • Most patients are likely to be anaemic due to chronic blood loss
      • High platelets as a response
  • Other paraneoplastic hormones - parathyroid hormone (high calcium), gonadotropins (masculinisation/feminisation), renin (high BP)
    • But normal presentation - loin pain, weight loss, haematuria

Case 3

  • Septic shock (fever, rigours,
    • Acute pyelonephritis
  • Prostate hyperplasia, blocks drainage from the bladder, urine stagnates in the bladder, becomes infected (cystitis) and the infection rises to the kidneys - pyelonephritis
  • Investigations
    • FBC
      • Increased WBC
      • ESR, CRP
      • Leucocytosis
  • Dipstick analysis (MSU)
    • Nitrates,
  • MCS - want to know what culture
  • Blood culture - enteric gram negative, gut organisms (E Coli, klebsiella, pseudomonas)
  • eGFR
  • Electrolytes, urine creatinine

Pathology autopsy

  • Inflammation of kidneys
    • Redness – dilation congestion of blood vessels
  • Increased areas of redness and congestion
    • Swelling and exudation
  • There is evidence of pus → yellow blobs (microabscesses) --> hence it is suppurative
    • Renal pelvis = pyelo
    • Nephros = kidney
    • There is inflammation of both kidney and collecting system → typically due to pyogenic bacteria
  • There is inflammation of both kidney and collecting system → typically due to pyogenic bacteria
  • Cause
    • Stasis of urine in the bladder → increased residual urine volume → infection → E. Coli have pili which help them attach to wall → when there is obstruction, there might be reflux → there needs to be reflux of urine for the organism to ascend up to the kidneys
  • Cystitis
    • Pain – dysuria
      • Increased frequency – polyuria
    • Loin pain
    • Swelling and distension of renal capsule
  • Fever
    • Release of inflammatory cytokines – TNF-alpha and Il-1→ resetting of hypothalamic thermostat → release of prostaglandin E2 → fever
    • NB
  • Once organism enters kidney → can enter blood stream → Lipopolysacharide (endotoxins) on bacteria triggers of massive release of IL and TNF-alpha -->widespread dilatation of blood vessels → decreased peripheral vascular resistance --> lower blood pressure → shock → decreased perfusion to vital organs → death
    • Organs don't get enough blood supply
    • Decreased myocardial contractility - decreased blood flow (lower blood pressure) --> lower cardiac output
    • Disrupted endothelium due to LPS --> procoagulant (tissue factor, tissue thromboplastin), less anticoagulant (less thrombomodulin) --> platelets stick more readily to the endothelium --> thrombi form, even in capillaries --> disseminated intravascular coagulation (DIC)

Slide

Acute tubular necrosis, an important cause of acute kidney injury

  • Dead tubules (anucleated), glomerulus alive
  • This is because these tubules didn't get enough blood
  • Proximal tubules are the more metabolically active ones (need more ATP), so they die selectively
  • A lot of the glomeruli have brown fibrin inside them. Microthrombi have blocked up the circulation; so not much blood was coming out of efferent tubule, so not much blood going around to the next tubule --> death of metabolically active tubules
  • This is how DIC looks on a slide - little clots inside capillaries - looks similar in other tissues (brown blobs in capillaries)
  • MAHA - microangiopathic hemolytic anemia: red cells broken up trying to squeeze past microthrombi
  • DIC during pregnancy - amniotic fluid from the foetus sets off coagulation in the woman
    • Causes: damage to vessel wall (endothelial injury - overexpression of procoagulant), or changes to the contents of the blood (procoagulant substances)
      • Note that cancers can cause mucins that get into the circulation and behave like tissue factor and set off coagulation
      • Burns/extensive trauma can cause coagulation too

Case 4

  • Nephrotic syndrome: proteinuria >3.5, hypoalbuminaemia, hyperlipidaemia, oedema
  • This case is not nephrotic syndrome
  • Nephritic syndrome: haematuria, proteinuria
    • Inflammation --> bleeding in the urine; due to glomerulonephritis
  • Very small kidneys
    • Normal: 12x6x3 cm
    • Due to chronic glomerulonephritis, because nephrons are dying, and being replaced with scar tissue - collagen/fibrosis
  • Need to lose 80-90% of nephrons to get abnormal UEC (urea electrolyte creatinine)
  • High Urea and Creatinine --> high nitrogenous waste; because not enough nephrons --> accumulating waste
  • Symptoms: confusion, anorexia, nausea, vomiting, neuropathy, myopathy, coma
  • High K --> cardiac arrhythmias
  • Low NaCl, because he's retaining both NaCl and water, so dilation
  • Low HCO3 --> metabolic acidosis
  • Severe hypertension
    • Water retention, salt retention
    • Kidneys are underprofused --> producing renin

Causes of CKD

  • Granular contracted kidney can also be caused by diabetic nephropathy
  • Polycystic kidney disease - large cystic kidneys
  • Hypertension
  • Chronic obstructive uropathy
  • Chronic tubulointerstitial nephritis e.g. urate nephropathy
    • Hyperurecaemia from CKD --> crystallize in kidney, make things even worse
  • Chronic glomerulonephritis
  • Chronic obstructiveuropathy/chronic pyelonephritis e.g. vesicoureteric reflux
  • Low EPO production --> anaemia
  • 1-hydroxylation of vitamin D missing; less absorption of calcium
    • Stimulates parathyroid gland -- secondary hyperparathyroidism, bone pain etc (breaking down bone to raise Ca)

Chronic kidney disease

  • Irreversible - permanent destruction of nephrons
  • Nitrogen retention, metabolic acidosis, hyperkalaemia
  • Reduced EPO production, impaired vitamin D metabolism - metabolic bone disease

Case 5

  • Ballotable kidneys
  • Very large kidneys, lots of cysts, kidney parenchyma replaced by cysts/fibrous tissue, haemorrhage into the cysts
  • Adult Polycystic Kidney Disease
    • Inherited by autosomal dominant; high penetrance
    • Genes are PKD1, PKD2
      • Code for polycystin 1 and 2 (respectively)
      • Important with cell-to-cell and cell-to-matrix; expressed in tubular epithelium
      • Regulate calcium influx to cells
      • Mutation --> Unable to regulate the proliferation of tubular epithelial cells → proliferate and cause large cysts in the kidneys → interferes with renal function → Inflammation of kidneys contributes to gradual reduction of GFR
      • Mutation in PKD1 --> progression is faster
      • Retain function until 40 then gets worse. PKD1 (52), PKD2 (69).
      • Same problem occurs in smooth muscle cells of arteries at the base of the brain → increased risk of berry aneurysms → subarachnoid haemorrhage.
          • Presentation: sudden onset of worst headache ever
      • Hypertension due to loss of renal parenchyma
      • Can also occur in liver and pancreas, spleen, lungs
      • Mitral valve prolapse also occurs
      • Kidneys → loin pain (Dragging sensation)? Causes
        • Sudden enlargement due to haemorrhage into cysts --> stretches the capsule
        • Clot-colic of ureter → colicky pain (passing of a clot in urine)
        • Infection of stagnant urine in cysts → pain