Historical perspective of iatrogenic, drug-induced nephropathies

The modern concept of iatrogenic drug-induced nephropathies as a special group of renal disease was bornfollowing the first description of the “phenacetin* kidney” by Spühler and Zollinger in 1953 (*Phenacetin; acetophenetidin; acetophenetin).

No other drug-induced renal disease was as hotly debated as the “phenacetin kidney”. Great controversy arose for years, even decades, between  proponents and opponents of a causal connection between phenacetin consumption and nephropathy. No other renal disease has been the subject of such varied interpretations. Detracters of the cause-effect concept favoured genetic disturbances of phenacetin metabolism or immunologic factors, as well as concomitant exogenic factors like smoking. Removal of phenacetin from pain killers – around 50 years after the first description in Switzerland – brought the solution overnight: the “phenacetin kidney”, or as then falsely labelled “analgesic nephropathy“ disappeared from the daily clinical routine. Today medical students, nephrologists and even pathologists are no longer aware of this disease.

However, this scientific controversy alerted experts that drug application can have not only acute side effects (acute renal failure, proteinuria etc.), but that prolonged misuse of drugs may lead to renal injury and even renal insufficiency, that only becomes clinically apparent after a long period (“Timebomb”). The “phenacetin kidney” story is extremely instructive: today we are not just concerned with early recognition of drug-induced nephropathies and avoidance of repeated exposure, but instead aim to monitor patients undergoing long term treatment with potentially dangerous drugs to detect renal disturbances. Because the kidney never forgets: when substances cause glomerular obsolescence, tubular atrophy or interstitial fibrosis, the lesions are irreversible! Repeated exposure to a particular drug or to another substance causing similar injuries can result in cumulative damage and eventually renal insufficiency.

The chronicle of this particular renal disorder also teaches us to be very critical of the term “interstitial nephritis“. Originally, Zollinger considered the “phenacetin kidney” to be primarily “interstitial nephritis”, that can lead to papillary necrosis. Today we know that interstitial nephritis is an unspecific consequence, but not the cause of the renal disease. The interstitial inflammation seen in the “phenacetin kidney” is, as with inflammation in nephrohydrosis (urinary congestion in the kidney), purely lympho-histiocytic without accompanying tubulitis, the consequence of urinary congestion.

However, the “phenacetin kidney” teaches us a further rule: we do not see everything in the renal biopsy! In the course of my 40 years of practice, I have only made a single diagnosis of “phenacetin kidney” (1/15,000 native kidney biopsies), but have with certainty misinterpreted further cases, where the biopsy did not contain papillary tissue. Without accompanying, careful study of nephrectomies and autopsies, drug induced lesions within the medulla, especially in the papilla, will continue to escape our attention.

Even when we consider 1953 to be the year in which consideration of iatrogenic and especially drug-induced renal injuries began, this does not mean that injuries due to drug treatment or other external noxia had not been recognised earlier.

In a handbook of special pathology and anatomy and histology by O.Lubarsch and F.Henke in 1925 and 1934, Th. Fahr mentions a limited number of exogenic noxia that caused nephropathy: Tribromoethanol (Avertin), tryptaflavin, sublimate (HgCl²), lead, chromium, uranium, arsenic, silver, cantharidin, salvarsan, bismuth as well as acids and chemicals, that result in haemo- or myoglobinuria (potassium chlorate, arsine, bismuth, carbolic acid, glycerine, toluene diamine, potassium iodide, pyrogallol, sulphuric acid).

More than 30 years later, in the Handbook “Niere und Ableitende Harnwege“ by H. U. Zollinger, we find a marked increase in the number of exogenic noxia accused of causing nephropathy.

Under the heading “Lipoidnephrose or Glomerulonephritis”, sublimate, calomel, mercuric diuretics, gold, mercuro-chromium, uranium nitrate, - all metallic noxia, as well as arsenic,salvarsan (arsphenamine), perchlorate, croton oil, and polyvinylaldehyde are also mentioned.

Of special interest is the detailed description of “nodular glomerulosclerosis” after carbon disulphide intoxication.

The majority of the noxia listed induced variable tubular injuries and sometimes tubular necrosis: calcium versenate, glycol-containing noxia (ethylenglycol, diaethylenglycol, glycolic acid, glysanthine), phenindione, cantharidin, mycotic toxins, phosgene, uranium nitrate, dioxan, sulfonamide, as well as antibiotics like neomycin and viomycin. Numerous noxia can also cause a haemoglobulin- and/or myoglobulin-kidney, amongst others: formic acid intoxication, tetrahydrocarbons, potassium chlorate, snake poisons. Lon-term collargol therapy is mentioned as cause of argyrosis. Lead and bismuth nephropathies have attracted considerable attention. Iron saccharate causes hemsiderosis of the kidney, lead results in a complex lead nephropathy with involvement of both, tubuli and blood vessels.

Nephropathies with pathological deposits include: Oxalosis following intoxication with noxia containing glycol, oxalic acid or salt of sorrel, nephrocalcinosis following vitamin D intoxication and finally crystallosis after sulfonamide usage.

Drug-induced urolithiasis has been associated with consumption of benemide, sulfonamides, diamox, vitamin B, dicumarol, oxamide und cytostatic agents.

Damage due to radiation treatment or thorotrast use has also been extensively discussed.

Noteworthy is the relatively low importance assigned to interstitial nephritis in connection with drug related injury. In the case of acute interstitial nephritis, sulfonomides, chlorpromazine, irgapyrin and phenylbutazone are cited and, in chronic cases, fluoride and naturally phenacetin. No drug is mentioned under the headings “renal cortical necrosis“ and “thrombotic microangiopathy“.

As a search of the handbooks reveals, many renal side effects are due to application of metallic noxia. If we consider the fact that metallic noxia have been popular since the start of pharmacotherapy, then renal side effects must have been present from the beginning.

Paracelsus (Philippus Theophrastus Aureolus Bombast von Hohenheim, christened as Theophrastus Bombastus von Hohenheim), known as Paracelsus, (* probably born 10. November 1493 in Egg near Einsiedeln (Switzerland); † 24. September 1541 in Salzburg) favoured mercury, sulphur and salts for therapeutic purposes.

Against this historical background it becomes evident that the term drug-induced nephropathy includes a variety of renal lesions which can be assigned rather specifically to certain drugs. Such associations require, however, targeted bioptic analysis for old and new drugs in the future.

• Th. Fahr u.a.: Harnorgane, Männliche Geschlechtsorgane. Vol. VI, 1 (1925);
  Niere und ableitende Harnwege Vol. VI.2 (1934)
  In:Handbuch der speziellen Pathologie und Anatomie und Histologie von O. Lubarsch und F.Henke (Hrsg.)
  Berlin Verlag Julius Springer
   
• H.U. Zollinger Niere und ableitende Harnwege Vol. 3 (1966)
  In: Spezielle pathologische Anatomie Hrsg. W. Doerr und E. Uehlinger,
  Springer Verlag Berlin Heidelberg New York.
   
• Paracelsus Septem Defensiones 1538, Basel