NSAID-Nephropathy
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Treatment with certain analgesics, named non-steroidal- antiinflammatory drugs, or NSAID, may in rare circumstances induce a renal disease. In some patients the disease develops in the course of a few days with a clinical picture similar to so-called acute tubular, acute tubulo-interstitial, or acute interstital nephritis with allergic symptoms, such as rash, fever, eosinophilia and acute renal failure. In most patients the disease develops more insidiously with heavy proteinuria, a slowly worsening of the kidney function and a rising blood pressure. A microscopic investigation of a kidney biopsy specimen may in some patients reveal almost normal glomeruli as in so-called minimal change nephropathy. Other patients may have more or less pronounced depositions of immune components in the glomeruli in a pattern similar to membranous glomerulonephritis. In a few patients other glomerulonephritis subgroups are seen. Almost all patients have tubular, interstitial or tubulointerstitial changes.
As
mentioned, NSAID nephropathy may often be followed by a reduced kidney function and the disease may progress to end-stage renal failure unless NSAID treatment is
discontinued. If so, almost all patients recover, most of them with normal renal
function.
The various clinical and laboratory appearances of NSAID nephropathy has led to the idea that
the mechanisms behind them also vary. However, in an analysis of 97 case
histories published in
medical journals a pattern emerged that was suggestive of a common allergic
mechanism (Ravnskov
1999). As the findings may have
importance for an understanding of the mechanisms behind glomerulonephritis in
general I shall shortly recapitulate them.
Three main groups of nephritis were recorded, 19 patients with acute tubular, interstitial or tubulointerstitial nephritis (to be short grouped together as "acute nephritis" in the following), 38 patients with minimal change nephropathy and 19 patients with membranous glomerulonephritis. A few other types were seen also, but they were too few to allow a systematic analysis.
It appeared that signs and symptoms of allergy were found in all the three main variants, most often in patients with acute NSAID nephropathy, least often in patients with membranous glomerulonephritis.
It was also obvious that the NSAID treatment time before the start of the disease differed substantially. Patients with acute nephritis had taken NSAID for on average 1.7 months, patients with minimal change nephropathy for on average 8.2 months, and patients with membranous glomerulonephritis for on average 39 months.
As is typical for most cases of acute nephritis due to other causes proteinuria was least pronounced in the acute NSAID nephritis, whereas heavy proteinuria was prevalent in the two other varieties, most pronounced in patients with minimal change nephropathy. In fact, the degree of proteinuria was independent on the amount of immune deposits in the glomeruli, in accordance with what I mentioned in the section Immunofluorescence Microscopy.
A typical finding on a kidney
biopsy from patients with glomerulonephritis and heavy proteinuria is swelling and fusion of the
podocytes, the glomerular epithelial cells. In
accordance, such changes were found in all of the patients
with minimal change nephropathy and membranous glomerulonephritis, but patients with acute NSAID nephritis had
podocyte fusion also,
although to a lesser degree, in support of a common mechanism behind all three
types of NSAID nephropathy.
The general finding of podocyte swelling is suggestive of an allergic reaction
involving activation of lymphocytes. It is well-known that activated lymphocytes
may produce chemical substances, so-called lymphokines,
that increase the permeability of the glomerular filters. Little attention has
been raised to the fact that fusion of the podocytes is seen in most cases of
acute nephritis due to other drugs also, although to a lesser
degree than in glomerulonephritis, possibly because there is a time lag before
the production of lymphokines is maximal (Ravnskov
1999).
Most important was that the renal function in NSAID nephropathy was strongly associated with the tubulointerstitial changes and strongly inversely associated with the amount of immune deposits in the glomeruli. The logical interpretation of this finding is of course that the primary damage is located to the tubulointerstitial tissue and that the glomerular changes are secondary and without importance for renal function. If the reaction against the NSAID is violent, the course is more dramatic and renal failure is prevalent, but with a short course, few if any immune components are deposited in the glomerular filters. With a milder and more protracted cause, time will allow more macromolecules to be caught in the glomeruli.
A relevant question: In most patients with acute nephritis due to an allergic reaction to a drug the kidney disease appears abruptly and the course is rapid and violent. If NSAID nephropathy is the result of an allergic reaction also, why is the course generally much more slow and why are the typical allergic symptoms absent in many patients, in particular those with a protracted course of the disease? The explanation may be that NSAIDs inhibit a variety of immunologic reactions, the very effect that has made these drugs suitable for treatment of inflammatory diseases. Most probably the milder course in NSAID nephropathy compared with acute nephritis induced by other drugs is due to a delay of the immunologic reactions induced by the offending NSAID itself causing the immune system to work ineffectively and in slow motion.
In conclusion, it is suggested that the various kidney diseases seen after NSAID treatment are not separate entities, but varying results of a common mechanism, an allergic reaction to the drug. In case the allergic reaction is strong and the effects of the offending drug on the immune system are weak, the patient will present with acute tubular, interstitial or tubulointerstitial nephritis. In case the allergic reaction is moderate, time will allow the lymphocytes that participate in the allergic reaction to produce lymphokines with unfavourable effects on the podocytes leading to heavy proteinuria. In case the allergic reaction is weak or the effects of the offending NSAID on the immune system is strong, the course will be even more protracted and as a result immune complexes, present in the blood circulation now and then, even in healthy individuals, will be caught in the glomeruli. The immune deposits are not causing the disease, they are secondary to the glomerular damage that is produced by the allergic reactions in the body.
Are
allergic mechanisms participating also in glomerulonephritis associated with exposure to toxic chemicals? This is suggestive from one of the animal experiments. By exposing mice to
carbon tetrachloride the researchers induced a mesangial
glomerulonephritis with deposition of IgG
in the glomeruli. However, if the mice were irradiated before the exposure no
glomerulonephritis was seen (Ogawa et al 1992
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