Acute Tubular Nephritis

• Most diseases involving the tubular system involve the interstitium as well
• ATN is characterised morphologically by destruction of tubular epithelial cells and clinically by acute loss of renal function
• It is the most common cause of acute renal failure but it therefore reversible

 

Causes;

• Ischaemia due to decreased blood flow e.g. hypovolaemia/shock (causing ischaemic ATN), PAN, malignant hypertension, haemolytic uraemic syndrome
• Direct toxic injury to the tubule e.g. by drugs (gentamycin), radio-contrast dyes, myoglobin, haemoglobin and radiation
• Acute tubulointerstitial nephritis – most commonly due to drug hypersensitivity
• DIC
• Urinary obstruction e.g. tumours, blood clots, prostatic hypertrophy

 

Pathogenesis

• The pathology underlying both ischaemic and nephrotoxic ATN are;
• Tubular injury
• Persistent and severe disturbance in blood flow
• Tubular injury
  • The tubular epithelial cells are particular susceptible to ischaemic injury due to;
  • Vast charged surface for reabsorption
  • Active transport systems for ions and organic acids
  • High metabolic rate and oxygen consumption
  • Ischaemia has a number of effects including, cell swelling, blebbing, loss of brush border, polarity and attachment. This can lead to necrosis or apoptosis
  • Due to loss of polarity there is redistribution of membrane proteins such as the Na-K ATPAse, which results in abnormal sodium transport across the cell and increased levels of salt reaching the distal tubules – this results in vasoconstriction via the renin-angiotensin system
  • Ischaemic tubular cells express ICAM-1 which recruits leukocytes – injurious inflammation
  • There is tubular obstruction resulting in a loss of GFR and an increased intratubular pressure
  • Fluid leads from the tubules into the interstitium resulting in interstitial oedema, increased interstitial pressure and further tubule damage
• Disturbances in blood flow
  • Intrarenal vasoconstriction occurs via the renin-angiotensin system (increased salt being deliver to the distal tubules)
  • Release of the vasoconstrictor endothelin (due to endothelial cell injury) and decreased levels of the vasodilator NO and PGI₂
  • There is also a direct effect of ischaemia on the glomerulus resulting in a mesangial contraction and a reduced ultrafiltration coefficient

 

• As injury is patchy, repair can occur if the cause is removed. Repair is based on reversibly injured epithelial cells proliferating and differentiating.
• Important factors in repair are EGF, TGF-a, insulin-like growth factor type I and hepatocyte growth factor

 

Morphology

• Ischaemic ATN is characterised by multiple foci of tubular epithelial necrosis with large sick lesions in between. There is rupture of the basement membrane and occlusion of the lumen by casts
• The straight portion of the proximal tubule and ascending thick limb in the medulla are particularly vulnerable
• Casts are particularly found in the distal tubules and collecting ducts and consist of Tamm-Horsfall protein – a urinary glycoprotein normally secreted by the cells of the ascending thick limb and distal tubules, as well as haemoglobin, myoglobin and other plasma proteins
• In toxic ATN necrosis is less patchy and is particularly evident in the proximal convolute tubule.
• The type of cell injury seem may depend on the toxic agent

 

Clinical course

• Classically the course of ATN can be divided into initiation, maintenance and recovery
• Initiation phase
  • Dominated by the injurious event
  • Only evidence of renal impairment is a slight drop in urine output and a rise in BUN (blood urea nitrogen)
• Maintenance phase
  • Characterised by sustained decrease in urine output to between 40-400ml/day
  • Salt and water overload
  • Hyperkalaemia
  • Metabolic acidosis
  • Treat patient by balancing water and electrolytes and dialysis
• Recovery phase
  • Characterised by a steady increase in urine output that may reach 3l/day
  • Large amounts of water, sodium and potassium are lost in the urinary flood
  • Patients are particularly vulnerable to infection at this stage
  • Eventually tubular function is restored, concentrating ability improves and the BUN and creatine levels return to normal

 

• Up to 50% of patients with ATN might not have oligouria and might instead have increased urinary volumes. This is called NONOLIGOURIC ATN and particularly follows damage with nephrotoxins. It generally follows a more benign course