Drug-induced nephropathies

In 1878, Jean-Martin Charcot (1825-1893) described the clinical picture of acute interstitial nephritis for the first time (Risler 2008 / Eknoyan 2011). In 1897, Councilman reported a total of 8 cases of acute interstitial nephritis as a result of an immunological reaction (Kasper 2015).

Drug-induced kidney damage causes tubulointerstitial kidney disease, which can be acute or chronic.

The acute form is characterized by the occurrence of inflammatory infiltrates in the area of the interstitium of the kidney and represents a special form of acute kidney failure.

The chronic form, on the other hand, leads to scarring in the area of the tubular interstitium.

(Kuhlmann 2015)

Drug-induced kidney damage can be caused in two ways:

• by an allergic-immunological reaction (so-called tubulointerstitial nephritis [Keller 2010]). This can be triggered by practically all drugs, typical representatives being diuretics such as furosemide or hydrochlorothiazide.
• by tubulotoxic effects (so-called tubulointerstitial nephropathy [Keller 2010]). These drugs cause dose-dependent damage to the kidneys. These include, for example, chemotherapeutic agents with platinum derivatives and many others (Risler 2008).

The drug-induced kidney damage is divided into:

• 1. acute toxic: Here there is a dose-dependent damage to the kidneys with e.g. aminoglycosides, cephalosporins, quinolones (Herold 2021).
• 2. chronic toxic: Chronic toxic kidney damage is also dose-dependent. They can be caused, for example, by paracetamol, phenacetin (Herold 2021).
• 3. hypersensitivity reaction: this occurs independently of dose and leads to acute tubular necrosis (ATN). (Herold 2021)
• 4. acute renal failure:

Acute renal failure can also occur in the setting of drug administration, e.g., by:

• Lipid lowering agents e.g:
  • CSE inhibitors
  • Fibrates
• Anticholinergics
• Neuroleptics
• X-ray contrast media
• Transfusion incident
• Drug abuse, etc. (Herold 2021)

Drug-induced kidney damage is found in unselected collectives in approx. 2 % - 3 % of all kidney biopsies (Risler 2008).

The acute form complicates about 5 % - 7 % of all hospital treatments in peripheral wards and about 30 % in intensive care units. Since 1980, this number has more than quadrupled.

However, the incidence is probably much higher, since a creatinine increase is often followed by an immediate change of preparation (Kasper 2015).

• Acute interstitial nephritis:

Drugs of various substance groups can cause acute interstitial nephritis. NSAIDs in particular can also trigger acute renal failure or minimal change glomerulonephritis (Keller 2010).

Drugs that can cause acute interstitial nephritis include:

• Antibiotics such as.
  • Aciclovir
  • Betalactams
  • Quinolones
  • Erythromycin
  • Ethambutol
  • Linezolid
  • Minocycline
  • Rifampicin
  • Sulfonamides
  • Vancomycin (Kasper 2015)
• Non-steroidal anti-inflammatory drugs such as:
  • Acetylsalicylic acid
  • Ibuprofen
  • Indometacin
  • Mesalazine
  • Naproxen (Kuhlmann 2015)
  • COX- 2 inhibitors
• Diuretics such as:
  • Loop diuretics
  • Thiazides
  • Triamterene
• Antiepileptic drugs such as:
  • Carbamazepine
  • Phenobarbital
  • Phenytoin
  • Valproic acid
• various drugs such as:
  • Allopurinol
  • Captopril
  • H2 blockers
  • Indinavir
  • Lenalidomide
  • Mesalazine
  • Proton pump inhibitors (Kasper 2015)
• Chemotherapeutic agents (rare)
• monoclonal antibodies such as:
  • Bevacizumab
  • Ipilimumab (Kuhlmann 2015)
• Chronic interstitial nephritis:

In the chronic form, drugs are also one of the common precipitating causes.

Medications include, for example:

• Analgesics (best known representative is analgesic anphropathy (Keller 2010):
  • especially mixed preparations
  • preparations containing phenacetin
• Lead
• Calcineurin inhibitors, e.g.
  • Ciclosporin
  • Tacrolimus
• cadmium
• Lithium
• Aristolochic acid (found especially in Chinese herbs) (Kasper 2015).

Drugs can cause vascular, tubulo- toxic, tubulo- obstructive and immunological interstitial damage at a total of 5 sites in the nephron:

1. vascular: This may involve a decrease in glomerular filtration rate (GFR) due to:

• a preglomerular vasoconstriction (with ciclosporin, tacrolimus, etc.)
• vasodilation (with ACE inhibitors, etc.)
• a thrombotic microangiopathy (with ciclosporin, mitomycin, tacrolimus etc.) (Risler 2008).

2. glomerulus: glomerular damage causes proteinuria and a decrease in GFR. This can be caused by penicillin, interferons etc. (Risler 2008).

3rd tubule cell: In this case, the phospholipid structure of the lysosomes is destroyed intracellularly by drugs such as aminoglycosides and necrosis of the tubules occurs (Risler 2008).

4. tubule lumen: The drug aciclovir is the preferred cause of damage to the tubule lumen. This crystallises tubularly when applied too quickly or in too high a dose and precipitates. However, statins or fibrates can also cause damage to the tubular lumen, as these drugs can lead to rhabdomyolysis and the myoglobin clogs the tubules (Risler 2008).

5. interstitium: In principle, however, all drugs that cause an allergic reaction can cause this damage. Typical damages are lymphocytic infiltrates in the interstitium. A classic representative of this damage are non-steroidal anti-inflammatory drugs (NSAIDs) (Risler 2008).

Kidney damage caused by drugs can affect the kidney tissue differently:

• acute interstitial nephritis as the cause of acute kidney failure
• chronic interstitial nephritis
• acute renal damage
• interstitial nephropathy
• analgesic nephropathy (Keller 2010 / Risler 2008)

Acute interstitial nephritis: In acute drug-induced tubulointerstitial kidney disease, the following symptoms may occur:

• Fever
• symmetrical exanthema
• Eosinophilia
• moderate proteinuria
• Oliguria (occurs in about 60% [Kuhlmann 2015]).
• anuria (Kasper 2015)
• renal acidosis
• Fanconi syndrome
• electrolyte imbalance (Kuhlmann 2015)
• flank pain (capsular stretching pain)
• microhematuria (Risler 2008)

These typical symptoms are usually absent in interstitial nephritis triggered by NSAIDs. In this case, a large proteinuria is more likely to be found - in addition to an atypical symptomatology (Kasper 2015).

Chronic interstitial nephritis: Chronic drug-induced kidney damage usually causes hardly any symptoms. Therefore, the diagnosis can often be made very late (Risler 2008).

Any existing oliguriaor anuria is only mildly pronounced (Kuhlmann 2015).

Initial laboratory changes of interstitial nephritis are:

• an increase in serum creatinine by ≥ 0.3 mg / dl within 24 - 48 hours or a 50 % increase in the baseline value
• Reduction in the volume of urine for more than 6 hours of 0.5 ml / kg (Kasper 2015).

Risler (2008) even recommends that any sudden creatinine increase should first be considered suspicious of drug toxicity.

Chronic interstitial nephritis: Since abusive painkiller use is usually denied, the primary question here should be existing pain and then only after drugs taken for it (Risler 2008). In most cases, the duration of medication use is > 1 month (Kuhlmann 2015).

Sonography

Sonographic examination to determine kidney size is mandatory (Risler 2008).

• In acute interstitial nephritis, the kidneys may appear normal in size or enlarged (Kasper 2015).
• In the chronic form, there is shrinkage of the renal tissue (Kuhlmann 2015).

Native computed tomography

In V. a. a painkiller nephropathy, irregular contours and / or calcifications may be detectable on CT (Risler 2008).

Renal biopsy

The kidney biopsy is only necessary in certain cases such as:

• after discontinuation of medication, the kidney function does not improve
• in the case of acute kidney failure requiring dialysis, which does not recover spontaneously and the cause remains unclear (Risler 2008).

Acute interstitial nephritis:

• Increase in creatinine
• Eosinophilia (found only in a few patients)
• Anemia
• Hyperkalemia
• Hyperphosphatemia
• Hypocalcemia
• Microhematuria (Kasper 2015).
• Appearance of leukocytes and leukocyte cells in the urine sediment
• Eosinuria
• Pyuria
• moderate proteinuria (Keller 2010)

Chronic interstitial nephritis:

• Anemia
• Hyperkalemia
• Hyperphosphatemia
• Hypocalcemia
• metabolic acidosis (Paumgartner 2013)
• In the urine sediment are found
  • sporadic erythrocytes
  • no erythrocyte cylinders
  • altogether few cells
  • leukocyturia
  • tubular epithelial cell cylinders (typical for the chronic form)
• Urine electrophoresis
  • low molecular weight proteins
  • Lysozymes
  • beta- 2- microglobulin
• proteinuria < 1.5 g / d
• Glucosuria
• Aminoaciduria (Kuhlmann 2015).

Acute interstitial nephritis:

• Edema in interstitium
• Cell infiltrates of eosinophils, monocytes, T- lymphocytes, neutrophils, plasma cells, rarely also granulomas (Keller 2010)

Chronic interstitial nephritis:

• Tubular atrophy
• infiltration of macrophages and lymphocytes
• interstitial fibrosis (Kuhlmann 2015)

Acute interstitial nephritis:

• acute immune complex glomerulonephritis
• acute tubular necrosis (Kuhlmann 2015)

Chronic interstitial nephritis:

• glomerular lesion

This can certainly only be clarified by biopsy. However, some differentiation is also possible by determining the alpha- 1- microglobulin in the urine and then calculating the quotients of urine / albumin or urine / protein (Kuhlmann 2015).

• Reflux nephropathy
• obstructive uropathy (Kuhlmann 2015)
• atheroembolic nephropathy (Kasper 2015)

• Uremia
• Hyper - or hypovolaemia
• Hyponatremia
• Hyperkalemia
• Acidosis
• Hyperphosphatemia
• Hypocalcemia
• Bleeding
• Infections
• Malnutrition
• cardiac complications

(Kasper 2015)

The immediate discontinuation of the triggering drug is obligatory. This leads to immediate improvement of symptoms in 70% of cases (Kuhlmann 2015).

Glucocorticoids: The administration of glucocorticoids seems to accelerate the recovery of renal function, but should be reserved for severe cases in which, for example, renal replacement therapy is pending or there is a further deterioration in renal values despite discontinuation of the triggering drug, on the one hand because of the risk of complications of immunosuppression (Kuhlmann 2015) and on the other hand because the long-term prognosis remains unaffected by the administration of corticosteroids (Kasper 2015).

Dosage suggestion: Initial 3 - 4 shocks of methylprednisolone of 250 mg - 500 mg and subsequent therapy with 1 mg / kg / bw prednisolone for 8 - 12 weeks (Kuhlmann 2015).

In the chronic form of the course should be refrained from corticosteroid therapy, as this does not lead to an improvement in renal performance (Kuhlmann 2015).

In addition to the above-mentioned discontinuation of the triggering drugs, only symptomatic measures are possible in this case, such as the occurrence of:

• Acidosis:

Elimination of acidosis, e.g. with acetolyte or acethol solution.

• anaemia:

administration of erythrocyte concentrates or erythropoietin

• Hypovolaemia:

administration of appropriate amounts of fluids adapted to hypovolaemia

• Electrolyte losses:

substitution of the missing electrolytes

• irreversible renal insufficiency:

renal replacement therapy or kidney transplantation (Paumgartner 2013)

The acute form of tubulointerstitial nephritis is usually reversible. In the chronic form of progression, discontinuation of the triggering drug can partially prevent progression of the nephropathy (Kuhlmann 2015).

Contrast nephropathy is reversible within one week (Risler 2008).

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