23. Acute tubular necrosis (ischaemic and toxic). Drug-induced (hypersensitive) interstitial nephritis, analgetic nephropathy, urate nephropathy. Acute and chronic pyelonephritis (pathogenesis, morphology, consequences and clinical course)

Last updated on May 18, 2019 at 10:19

Tubulointerstitial diseases

Many diseases don’t primarily affect the glomeruli but rather the tubules and interstitium. These diseases are called tubulointerstitial diseases. They can be caused by infections, obstruction, drug-related side effects and ischaemic effects.

Tubulointerstitial nephritis is commonly caused by bacterial infection. Another term, interstitial nephritis, indicates cases of tubulointerstitial diseases that are caused by causes other than bacterial infection.

Acute tubular necrosis

Morea about this topic can be studied in pathophysiology 1.

Acute tubular necrosis (ATN, also called acute tubular injury) is a condition characterized morphologically by damaged tubular epithelial cells and by acute decline in renal function. Granular casts and tubular cells are observed in the urine. Acute tubular necrosis is the most frequent cause of acute renal failure.

Many things can cause ATN, so we distinguish between the ischaemic form and toxic form:

  • Ischaemic ATN
    • Shock
    • Thromboembolism of renal artery
  • Toxic ATN
    • Iodinated contrast medium
    • Aminoglycosides (like gentamycin)
    • Pigment nephropathy
      • Myoglobinuria due to rhabdomyolysis
      • Haemoglobinuria due to haemolysis
    • Poisons
      • Heavy metals like mercury
      • Organic solvents

The tubules perform a lot of ATP-dependant transport and therefore have a large requirement for perfusion. When the tubules are ischaemic will they quickly be damaged. Especially the straight segment of the proximal tubule and the straight segment of the distal tubule (the thick ascending limb) are vulnerable to ischaemic damage.

Ischaemic tubular cells lose their polarity (meaning that membrane proteins move from their normal “side” to other surfaces of the cells). This causes the proximal tubules to be unable to reabsorb sodium, meaning that more sodium reaches the distal tubules. This activates the tubuloglomerular feedback, which decreases the GFR. As the cells lose their polarity, they also lose the “anchors” that keep them in place, causing them to detach from the basement membrane and shed into the urine.

If the shedding is excessive can the shedded cells block the outflow of urine. This increases the backward pressure in the tubules, which forces filtrate to leak through the damaged tubules and back into the interstitium, a process called backleak. Ischaemic tubular cells produce chemokines and cytokines that recruit inflammatory cells that cause interstitial inflammation.

Ischaemia also causes intrarenal vasoconstriction and activation of RAAS, which further decreases renal perfusion. Endothelial injury causes the endothelial cells to produce endothelin, which further reduces perfusion.

The pathogenesis is similar for toxic ATN. A small difference is that it is the convoluted segment of the proximal tubule which is most susceptible to toxic damage.

Ischaemic ATN is characterised histologically by lesions in the straight portions of the proximal tubule and ascending thick limbs. The lesions show focal necrosis and apoptosis. There are “skip lesions”, as there is a sharp border between segments that are affected and segments that aren’t. The tubules may be obstructed by casts. The interstitium is oedematous and has mild inflammatory infiltrate.

Toxic ATN is similar to the ischaemic type in histology, except a few things. Mainly the proximal convoluted tubules are affected. The basement membranes are generally spared from injury.

ATN follows three phases:

  • Initiation phase – Acute decrease in GFR, sudden azotaemia
  • Maintenance phase – Sustained reduction in GFR. Creatinine and BUN continue to rise
  • Recovery phase – Polyuria occurs as the tubular function is restored. Creatinine and BUN normalize

The prognosis is very good for the toxic form, but there is a more than 50% death rate in the ischaemic type as these cases often lead to acute renal failure.

Drug-induced interstitial nephritis

Drugs are an important cause of renal injury. Acute drug-induced interstitial nephritis occurs as an adverse reaction to many different drugs, which is why this condition is also called hypersensitive or allergic interstitial nephritis.

The following drugs are associated with nephritis:

  • Sulphonamide antibiotics
  • Synthetic penicillins like methicillin, ampicillin
  • Thiazides (a type of diuretic)
  • NSAIDs

The pathomechanism isn’t completely known. Some cases involve a type I hypersensitivity while others involve a type IV hypersensitivity. The drugs are most likely haptens that bind to proteins in the tubules to form immunogenic antigens. The resulting immune reactions damage the tubules and interstitium.

There is interstitial oedema and leukocyte infiltration. Tubules may show necrosis and regeneration.

The symptoms begin around 15 days after starting the drug treatment. Symptoms like fever, rash, haematuria, eosinophilia are common. 50% experience a rise in serum creatinine, however the prognosis is usually good.

Analgesic nephropathy

The most common cause of chronic interstitial nephritis is analgesic nephropathy. As the name suggests is it associated with chronic heavy use of painkillers like NSAIDs, paracetamol and phenacetin, a drug which is no longer used.

The pathomechanism involves a reduction in renal blood flow due to the decreased prostaglandin synthesis, which first causes necrosis of the papilla and later interstitial nephritis. Paracetamol damages the kidney by oxidative damage.

Affected patients may have polyuria, tubular acidosis and haematuria although they may be asymptomatic. Analgesic nephropathy increases the risk of urothelial carcinoma of the renal cell pelvis.

Acute urate nephropathy

Acute urate nephropathy is a complication of hyperuricaemia and gout. It causes a chronic interstitial nephropathy with uric acid crystal deposition in the stroma of the kidney, which initiates an inflammatory process.

It may also occur due to tumor lysis syndrome in patients who receive chemotherapy or radiation against tumors. As the tumor cells lyse as they die will they release uric acid (among other compounds), which can cause hyperuricaemia.

Pyelonephritis

Pyelonephritis is a bacterial infection of the renal pelvis. It’s usually due to an ascending bacterial infection from the bladder. The offending bacterium is most commonly gram-negative rods from the intestinal tract, most frequently E. coli and proteus. Pyelonephritis is most commonly acute, but it can be chronic in two cases, as we will see later.

In any pyelonephritis will there be bacteria in the urine, pyuria, proteinuria and WBC casts. Urinary casts are cylindrical structures (casts of the collecting ducts) that are formed in the collecting ducts and can be found in the urine. The casts can be comprised of RBCs, WBCs, bacteria and others.

Acute pyelonephritis commonly develops when a UTI in the lower urinary tract (urethra, bladder) ascends into the upper urinary tract (ureter, kidney). The risk factors for developing acute pyelonephritis are therefore very similar to the risks for developing lower urinary tract infection:

  • Female gender – as females have shorter urethras 💁🏻‍♀️
  • Sexy sex 🍆💦 – especially if you don’t pee the bacteria out after sex
  • Indwelling catheter
  • Diabetes mellitus – as the glucosuria is very attractive for bacteria
  • Immunosuppression
  • Urinary tract obstruction – as it causes urinary stasis
  • Vesicoureteral reflux – where urine is refluxed from the bladder to the ureter

Acute pyelonephritis can also be spread by the blood, which can occur in septicaemia or infective endocarditis.

Vesicoureteral reflux can be caused by anatomical abnormalities in the ureter or the valve that prevents reflux from the bladder to the ureter. It can also be caused by obstruction due to urinary tract infection or neurogenic bladder.

The bacteria attach to the renal tubules, initiating an inflammatory reaction and causing tubular necrosis. The inflammation is suppurative, so there is pus formation.

Some of the complications of acute pyelonephritis are:

  • Pyonephrosis – where the infection spreads to the collecting system
  • Perinephric abscess
  • Necrosis of the renal papilla
  • Urosepsis – sepsis that originates from the urinary tract

Patients with acute pyelonephritis can have high fever, dysuria, increased frequency of urination and pain at the costovertebral angle.

Chronic pyelonephritis occurs when there is recurrent or persistent acute pyelonephritis. It is mostly due to either obstruction of the urinary tract (by BPH, neurogenic bladder, nephrolithiasis) or due to vesicoureteral reflux. It can lead to chronic renal failure. The specific histological picture of chronic renal failure can be studied in the “hyalinized glomeruli” slide.

Xanthogranulomatous pyelonephritis is a benign lipidic neoplasm in the kidney that occurs due to inappropriate inflammatory response to a bacterial infection.


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24. Benign and malignant nephrosclerosis and diffuse cortical necrosis. Urolithiasis and obstructive uropathy.

4 thoughts on “23. Acute tubular necrosis (ischaemic and toxic). Drug-induced (hypersensitive) interstitial nephritis, analgetic nephropathy, urate nephropathy. Acute and chronic pyelonephritis (pathogenesis, morphology, consequences and clinical course)”

  1. firstable wanna say thank you for the clear and understandable note then i would like to mentioned you need to correct the dictation of vesicoureteral reflux..

  2. Aren’t myoglobinuria and haemoglobinuria toxic nephropathies? At least that’s what we learnt in pathophys, and I just googled it, wikipedia also says so. 🙂

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