4.1.2 Vacuolar ATN

Definition: Vacuolar transformation of the tubular epithelium without overt necrosis.

Vacuolar degeneration

Hydropic change:The most common form of fine vacuolar change of the tubular epithelium is hydropic change (“osmotic nephrosis”)

The morphology of osmotic nephrosis or “sucrose nephrosis” was studied in great detail in autopsies and animal experiments between 1940 and 1970. Nowadays, the results can be confirmed in biopsy material. The development of hydropic ATN (osmotic nephrosis) is obviously promoted by pre-existing renal damage with chronic renal failure or shock of any etiology.

At autopsy, the kidneys are enlarged and pale, thus exhibiting ATN-like changes. Histologically, hydropic ATN  is characterized by a focal or less often diffuse “clear cell” transformation of proximal tubular epithelial cells showing isometric fine vacuolization of the cytoplasm. The straight part of the proximal tubule is primarily involved and in severe cases also the convoluted part. Severely affected tubules are often seen side by side with tubules  of normal appearance. The distal tubules and the collecting ducts are more or less unchanged. Occasionally, parietal epithelial cells lining Bowman`s capsule, podocytes, or interstitial cells may be affected and show vacuoles.

Early changes of hydropic ATN  are tiny vesicles under the apical cell membrane. During further development, the number of vesicles increases gradually filling the cytoplasm. Probably due to fusion, the vacuoles increase in size from the apex to the basal parts of the cell, finally measuring 1-4 µ in diameter. Most vacuoles appear empty by light and electron microscopy. In late stages, the vacuoles may contain an amorphous electron dense material. The nucleus is gradually displaced to the basal part of the cell and becomes distorted by the adjacent vacuoles. Mitochondria and other cell organelles remain unchanged.

Tubular vacuolization causes gradual cell swelling and may lead to narrowing but not to complete occlusion of the tubular lumens. The brush border and the basal labyrinth are usually well preserved. By electron microscopy and enzyme histochemistry, the vacuoles were identified as lysosomes.

The sequelae of osmotic nephrosis are unpredictable since repeat biopsies are usually not performed. In most cases, the vacuolization will completely vanish without sequelae, as we have seen in one kidney transplant on repeat biopsies. In other cases with protracted renal failure, the vacuolization may persist without further significant morphological changes of the kidney. In a few cases with irreversible renal failure, tubular atrophy, interstitial fibrosis and accompanying inflammation must be expected. Interestingly, hydropic change of interstitial cells and endothelial cells of peritubular capillaries is often seen in patients treated with HAES, who develop terminal renal failure.

Hydropic damage is seen after administration of hypertonic infusion solutions, radiocontrast media, intravenous immunoglobulin administration (IVIG) and in Calcineurin inhibitor nephrotoxicity or plasma cell dyscrasia (mostly with kappa light chain storage in tubular cells). Of note, hydropic change may be present in patients without any of the above mentioned etiological factors.

Fatty change and foam cells:

Fine vacuolar change of the tubular cells is also seen in  case of lipid storage.

Lipid stains easily allow the differentiation between fatty change/ foam cells and hydropic change. In paraffin sections, the “hydropic change” may be  indistinguishable from lipid storage..

In fatty change the vacuoles are first seen at the basal aspect of the proximal tubular cells. Finally the entire cell show a vacuolar transformation (“foam cell”). In case of lipid storage, foam cells are often found in the interstitial space to an extent never seen in osmotic nephrosis.

Fatty change and foam cells may be seen in nephrotic syndrome, liver failure and intoxications.

Variants of vacuolar degeneration

Coarse vacuoles in the distal tubules are found in hypokalemia. The vacuoles are mainly found in distal tubules accompanied by PAS-positive granules in the collecting ducts. Hypokalemia must be severe and long standing independent of the etiology. Chronic laxative abuse may be one factor. A very few large vacuoles may be seen in proximal tubules after rapamycin therapy.

Irregular fine and coarse vacuoles are present in ischemic renal damage; the proximal tubules contain vacuoles of variable size accompanied by a loss of the brush border, bleb formation, often a desquamation of the epithelium from the basement membrane and signs of regeneration.

Coarse and even giant vacuoles mainly in the proximal tubules are found in case of ethylenglycol and diethylenglycol intoxication. Oxalate crystals in large amounts are present in ethylenglycol but not in diethylenglycol intoxication.

Water clear transformation of the epithelial cells is today rarely seen in massive  diabetic hyperglycemia (of long duration), in gycogenosis or carcinomas.