Interstitial nephritis and acute tubular necrosis in the dog and cat

Interstitial nephritis is an inflammatory process of the kidneys with a variety of aetiologies. It mainly affects the renal interstitium and tubules and, since it can be associated with damage to the renal tubules, it is often called acute or chronic tubulo-interstitial nephritis. The tubulo-interstitial nephritides are classified histologically on the basis of morphological characteristics visible by optical microscopy. Acute, sub-acute and chronic forms of tubulo-interstitial nephritis can be distinguished._¹

• In the acute nephritides there is a multifocal distribution of infiltrate consisting mainly of polymorphonuclear cells in both the interstitium and within the lumen of the renal tubules (tubulitis). The epithelium of the tubules may show focal areas of degenerative phenomena and necrosis of the epithelium itself. Oedema and, in some cases, haemorrhage may be present in the interstitium.

• In the sub-acute nephritides the inflammatory infiltrate is mixed, with lymphocytes, plasma cells and rare neutrophils (more rarely, oesinophils). The epithelial cells of the renal tubules show various degrees of degeneration manifested by (micro-macro) vacuolisation, apoptosis, intracytoplasmic pigment and vacuolar degeneration. In addition, there may be rare signs of necrosis, with mineralisation of the tubules; sometimes evidence of regeneration is present. The regenerative phenomena are pathophysiologically related to the capacity of the tubular epithelium to regenerate and, therefore, to the severity and extent of the damage. Increased numbers of fibroblasts and deposition of extracellular matrix are compatible with chronically evolving renal damage. The glomeruli may be involved secondarily by the inflammatory process. At the same time, sclerotic glomeruli, thickening of Bowman’s capsule and atrophy of the whole nephron can be seen.

• 

  The chronic interstitial nephritides are the outcome of the above describedprocesses occurring in the acute and sub-acute forms. Histological examination rev eals a severe, extensive, chronic inflammation of the interstitium characterized by lymphocytes and plasma cells (rarely, mast cells). The tubular response to the inflammation includes atrophy of the tubules themselves, thickening of the tubular basement membrane, cystic dilatations and the presence of protein casts. The extensive fibrosis is the kidney’s defence strategy to halt the inflammatory process (Fig. 1). Arteriosclerosis is sometimes present._¹

The aetiological agents most widely recognized as being able to cause interstitial nephritis in the dog are: type 1 Adenovirus, Herpesvirus and Hepatozoon canis._² In the cat only one aetiological agent, Feline coronavirus, has been reported to cause pyogranulomatous nephritis.

LEPTOSPIRAL NEPHRITIS

Leptospirosis is one of the most common diseases able to cause interstitial nephritis in the dog. Following a brief period of bacteraemia, the leptospirae localise in the epithelium of the proximal tubule. The leptospirae penetrate through the conjunctival and buccal mucosae and possible breaches in the skin. The target organs after the phase of bacteraemia are the liver and kidney, but the spleen and central nervous system may also be involved. Clinically, the animals have darkish red urine. The invasion of the tubular epithelial cells by the leptospirae is associated with polyuria and dehydration. The severity of the infections very often differs depending on the serotype of the bacterium: the serotypes grippotyphosa and pomonaare associated with more severe symptoms of renal failure._³

In the kidney the damage is predominantly acute, with initial signs of acute interstitial nephritis and multifocal necrosis. Renal failure is a consequence of direct toxic damage to the tubules or the result of hypovolaemia in systemic infections. Experimental studies have demonstrated that leptospirae within the tubule can attract inflammatory cells (T lymphocytes) through the expression of type II molecules of the major histocompatibility complex. This complex is also expressed by the renal tubule epithelial cells involved in the inflammatory process._⁴ The leptospirae within the tubules may be identified during histological examination of a renal biopsy by staining with a specific solution called Warthin Starry stain._³

INHERITED INTERSTITIAL NEPHRITIDES

The role of inherited interstitial nephritides deserves a chapter apart. These nephritides have been studied in Bull Terriers, Dalmatians and Samoyeds and are involved in progressive forms of chronic renal damage. These breeds have been studied and selected as models for Alport’s syndrome in humans. The pathognomonic characteristic of this disease is progressive delamination of the glomerular basement membrane with clinical signs of microalbuminuria, albuminuria, haematuria and progressive renal failure. The pedigree shows vertical transmission from a sire to a male offspring and mutations involve two specific genes: COL4A3 and COL4A4._⁵ Histologically there is a mixed pattern of lesions which involve both the glomeruli (foetal glomeruli, mesangial proliferation, segmental or global sclerosis, periglomerular fibrosis) and the tubulo-interstitial compartment (tubular atrophy, mineralisation of the basement membrane of the renal tubules, intratubular protein casts and moderate to severe fibrosis).

ACUTE TUBULAR NECROSIS

Acute tubular damage is manifested clinically by acute renal failure and histologically by signs of acute tubular necrosis. There are two main pathophysiological mechanisms:

Ischaemic tubular necrosis: the ischaemia may be a consequence of hypovolaemic shock of any cause (e.g. post-traumatic, post-operative, haemorrhagic,  severe hypotension, severe dehydration, sepsis). In this case the blood flow in the peritubular capillaries is reduced and there is a decrease in the glomerular ultrafiltrate. Furthermore, toxic substances produced during hypovolaemic shock cause direct damage to the renal tubule epithelial cells.

Nephrotoxic tubular necrosis: a series of toxic substances, such as mercury, carbon tetrachloride, insecticides, some drugs – including antibiotics, barbiturates, antineoplastic agents, non-steroidal anti-inflammatory drugs – and liquid contrast agents used in radiological examinations, have acute direct or indirect toxic effects on tubular epithelial cells. In contrast to ischaemic damage, which involves large parts of the nephron, these toxic substances have a selective action on specific parts of the tubule.

The characteristic histological changes in tubular necrosis can be divided into three main types of lesions:

1. foci of necrosis in multiple parts of the nephron
2. alterations of the basement membrane (tubulorrhexis)
3. acute/subacute inflammatory infiltrate of the interstitium (predominantly polymorphonuclear cells)

The distribution of the lesions differs depending on whether they are caused by ischaemia or toxic factors: in the hypoxic forms the lesions essentially involve the proximal convoluted tubule and loop of Henle, whereas in the toxic forms, there is diffuse involvement of the whole proximal convoluted tubule.

The prognosis of dogs with acute tubular necrosis is related to:

• extent of the damage
• treatment and promptness of the intervention
• regenerative capacity of the tubular epithelium

The damage is considered reversible when there is complete recovery or when fibrotic processes that isolate the lesions are established. Histologically reversible damage is characterized by a loss of cell polarity, focal tubular necrosis and maintenance of the morphological integrity of the renal tubule basement membrane. This last point is fundamental for recovery to normal since the basement membrane is the component from which the damaged epithelium is regenerated. The integrity of the basement membrane can only be evaluated by electron microscopy, but is an important factor for the prognosis of the animal.

Irreversible damage to the tubules occurs after toxic damage with extensive necrosis of several parts of the renal tubule and damage to the basement membrane of the tubules.

References

1. Canine chronic renal disease: prevalence and types of glomerulonephritis in the dog. Macdougall DF, Cook T, Steward AP, Cattell V. Kidney Int. 1986 Jun;29(6):1144-51.
2. Control of canine leptospirosis in Europe: time for a change? Ellis WA. Vet Rec. 2010 Oct 16;167(16):602-5.
3. Expression of class II major histocompatibility complex molecules in renal tubular epithelial cells of canine kidneys affected with tubulointerstitial nephritis. Vilafranca M, Wohlsein P, Trautwein G. Res Vet Sci. 1995 Sep;59(2):114-7.4.
4. Hepatozoonosis in dogs: 22 cases (1989-1994). Macintire DK, Vincent-Johnson N, Dillon AR, Blagburn B, Lindsay D, Whitley EM, Banfield C. J Am Vet Med Assoc. 1997 Apr 1;210(7):916-22.
5. Renal pathology of polycystic kidney disease and concurrent hereditary nephritis in Bull Terriers. O'Leary CA, Ghoddusi M, Huxtable CR. Aust Vet J. 2002 Jun;80(6):353-61.