Types of Tubulointerstitial Diseases

Acute and Chronic Tubulointerstitial Nephritis 

• This is characterized by interstitial inflammatory cell infiltrates associated with tubular necrosis of varying severity in acute cases and tubular atrophy and fibrosis in chronic cases.
• There is much more interstitial cell infiltrate than what is seen in acute tubular necrosis.
• The infiltrate can be neutrophils but, more often, is mononuclear cells, including CD8 and CD4 T cells, plasma cells, and histocytes.
• There is always some underlying acute tubular necrosis and direct injury to the cells that is covered by the inflammatory infiltration.
• There are three classes of tubulo-interstitial nephritis (Tubulo-interstitial Neprhitis):
  • Reactive infectious Tubulo-interstitial Neprhitis
    • This is mediated by pro-inflammatory cytokines.
    • The organisms are usually not identifiable.
  • Drug induced Tubulo-interstitial Neprhitis – This can include:
    • Beta-lactam antibiotics (like cephalosporins)
    • Methicillin
    • Sulfonamides
    • Rifampin
    • Vancomycin
    • NSAID
    • Phenytoin
    • Diuretics (like furosemide and thiazides)
    • Analgesic nephropathy – common in Scandinavian countries.

o        Requires excessive and prolonged use of analgesics (2-5 g phenacetin over 2-3 yrs)

o        Characterized by papillary necrosis, cortical scarring, extensive tubular atrophy, tubulointerstitial fibrosis, and microangiopahty of the papillae (see image to the right if you don’t remember what papillae are).

o        Patients have a higher incidience of transitional papillary tumors of the pelvis and calyces (see image for calyces).

• Immunological Tubulo-interstitial Neprhitis – this can be antibody or cell-mediated.
  • Anti-TBM antibodies
  • Immune complex deposition – the immune complexes get deposited in the intertubular capillary walls and cause local inflammation and infiltrates.
  • Cell mediated (like allogenic reactions)
• Miscellaneous
  • Lead nephropathy – you can see inclusions within the cells, which are diagnostic for lead poisoning.  These Pb-NP (NP = nucleoprotein) complexes can lead to interstitial fibrosis.

o        Also chronic.

• Balkan nephropathy – an endemic chronic interstitial nephropathy prevalent in isolated areas of the Balkan region along the tributaries of the Danube River.

o        Characterized by progressive tubulointerstitial fibrosis

§         This leads to a profoundly concentric and symmetrical renal atrophy and ESRD.

o        Associated with a high frequency of urothelial cancer of the pelvis and the ureter and infrequently with focal papillary necrosis.

Synergistic Interaction in Acute Renal Failure 

• There are some factors that act synergistically to increase the patient’s risk for acute renal failure:
  • Volume depletion – about 20 – 30% of patients with volume depletion develop Acute Renal Failure
    • Diabetes mellitus – patients with volume depletion and DM have a 100x increased risk of Acute Renal Failure.
    • Nephrotoxins (cephalosporins, gentamycin, radiocontrast media) – 9x

• Shock – 10 – 20 % of patients with shock develop Acute Renal Failure; alone, shock causes a 35-45x increase in Acute Renal Failure risk.
  • Septicemia – increases the risk 100x
• Drugs (NSAID, Gentamycin)
  • CHF or liver cirrhosis – 3 – 6x
• Old age – 2 – 4x

Acute and Chronic Pyelonephritis  

This is due to bacterial infection and can be of two types:

• Hematogenous infection
• Ascending infection
  • Ascending obstructive infection
    • Prostate enlargement
    • Ureteric stones and tumors
    • Periureteric fibrosis
    • Xanthogranulomatous pyelonephritis – often associated with Proteus infections.
      • It’s rare and chronic
      • Characterized by distortion of renal architecture with patchy yellowish-orange discoloration and infiltration by foamy macrophages, plasma cells, lymphocytes, and polymorphonuclear leukocytes.
  • Ascending non-obstructive infection
    • Vesicoureteral reflux (congenital and acquired) – this may result in ascending infection but if the urine is sterile, it may be responsible for reflux nephropathy with glomerulosclerosis and nephrotic syndrome.  This occurs primarily in children.   Histologically, the tubules look necrotic and the cells actually look like a thyroid gland.
    • Neurogenic ureteral dysfunction – for example spinal injury can cause the ureter to remain dilated. This causes stasis of the urine which can lead to infection.
      • Can also happen in diabetics.
    • Surgical diversion of ureter – replacement of a person’s own bladder with a portion of their ileum. But since there is now no sphincter between this new “bladder” and the ureter, there is always reflux of urine.
• In acute pyelonephritis – there is patchy tubulo-interstitial infiltrate by polymorphonuclear leukocytes and abscess formation with healing by scarring.
• In chronic pyelonephritis – there are recurrent episodes of acute inflammation, tubular atrophy, and interstitial fibrosis, interstitial mononuclear cell infiltrate, thyroidization of tubules, and periglomerular fibrosis.
  • Also, in chronic pyelonephritis, the reflux affects only the upper and lower poles of the kidney (the compound calyces) – so the inflammation and fibrosis also happen at these poles.

Acute Papillary Necrosis

• Acute papillary necrosis is usually bilateral and can involve few or all papillae.
• The cortex is not involved – only the medulla.
• In the kidneys, you can see that the papilla has disconnected from the rest of the tissue.  If you inject it with radiocontrast dye, you will see a ring sign on retrograde pyelogram as the dye goes around the necrotic papilla. Therefore, the ring sign is very diagnostic of papillary necrosis.
• Sometimes, excreted necrotic papilla may be observed in the sediment of a centrifuged urine slide preparation by light microscopy.
• Patients will usually present with oliguria, acute loss of renal function, or renal insufficiency.  Necrosis usually begins with one papilla and if not treated, will result in bilateral papillary necrosis.
• Most common causes:

·         Diabetes is the most major cause.

·         As already mentioned, analgesic nephropathy is prevalent in many Scandinavian countries.  It requires excessive and prolonged use of analgesics (2 to 5 grams of phenacetin over 2 to 3 years) and is characterized by papillary necrosis, cortical scarring, and characteristic microangiopathy of the papillae.

·         Obstruction involves tumors or stones. 

Bilateral Renal Cortical Necrosis

·         This is a rare cause of acute renal failure and most often presents with anuria or oliguria.  The pathogenesis remains known, but severe vasospasm and thrombotic microangiopathy have been implicated as causal factors.  The renal vasculature becomes stenotic, leading to a loss of blood supply to the kidneys.

·         Light microscopically, it is characterized by bilateral ischemic cortical infarction.

·         Only the cortices are involved (not the medulla).  The extent of cortical involvement ranges from large areas to the entire cortex itself.

·         There are two main causes of bilateral renal cortical necrosis. 

o        Obstetric complications – this is the major cause of bilateral renal cortical necrosis (50 – 70% of cases).  This can involve abruption placenta and septic abortion.

o        Non-obstetric causes (20 – 30% of cases) – this can involve shock / DIC, acute pancreatitis, aortic dissection, and hyperacute allograft rejection.

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