Acute tubulointerstitial nephritis N10.-

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 02.02.2021

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Acute interstitial nephritis; Acute interstitial nephropathy; Acute tubulo-interstitial nephritis; Acute tubulointerstitial nephritis; AIN; ATIN; ATN, Acute tubulointerstitial nephritis; D-ATIN; Drug-induced ATIN; Interstitial Nephritis; TIN; Tubulointerstitial nephritis; Tubulointerstitial nephritis acute

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Acute tubulointerstitial nephritis (TIN) manifests itself clinically as a polyätiological, but predominantly drug-induced disease pattern, usually with acute to subacute renal failure. TIN can occur as primary damage to the tubulointerstitium or as secondary damage in the wake of glomerulopathy or as part of systemic diseases (e.g. Sjögren's syndrome, sarcoidosis).

In many kidney diseases that are associated with severe glomerular inflammation, a secondary TIN is added as a complicative concomitant disease (e.g. lupus nephritis or IgA nephropathy). The extent of this tubulointerstitial concomitant nephritis influences the prognosis of many glomerulopathies and significantly determines the progression of renal failure (Cohen CD et al. (2017).

While the typical course of renal failure in acute interstitial nephritis ranges from days to weeks, it can be significantly shorter, especially with re-exposure to a nephrotoxic drug. About 30% of patients require dialysis treatment during the course of the disease.

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With about 75% of all cases, drugs are among the most common triggers of TIN, followed by infections and autoimmune diseases. The following drugs can trigger a TIN:

  • Antibiotics (detected in 35% of patients): Vancomycin, Erythromycin, Vancomycin, Tetracyclines, Trimethoprim, Ethambutol, Gentamycin (Pingili CS et al. 2017)
  • Betalactam antibiotics: often classical triad (fever, eosinophilia, rash)
  • Sulfonamides: often classical triad (fever, eosinophilia, rash)
  • Fluoroquinolones: Mostly no systemic signs
  • Rifampicin: mainly for intermittent administration, combined with haemolytic anaemia, thrombopenia and hepatitis; antibody-mediated.
  • NSAIDs: diclofenac, fenoprofen, ibuprofen, naproxen, indomethacin, zomepirac, mefenamic acid, piroxicam, paracetamol, phenylbutazone, tolmedin (Inoue D et al. 2017). Clinical signs: Mostly no systemic signs, no eosinophilia, latency usually several months, often with nephrotic proteinuria (in addition glomerular changes in the sense of a minimal change disease or secondary membranous glomerulonephritis).
  • Diuretics: Thiazides, furosemide, triamterene, chlorthalidone, indapamide, etacrynic acid
  • Virustatics: e.g. Aciclovir
  • Proton pump inhibitors (detectable as triggers in 35% of patients - Valluri A et al. 2015); clinical: no systemic signs; sediment and proteinuria usually only mildly abnormal; long latency.
  • Various: Adalimumab, Infliximab, Cilostazol (phosphodiesterase 3 inhibitor), Captopril, Amlodipine, Ranitidine, Phenobarbital, Nitrofurantoin, Azathioprine, Oxaliplatin, Valproic acid, Carbamazepine, Interferon, Indinavir, Mesalazine, Isotretinoin (Castro Corredor D et al. 2019; Choi YJ et al. 2018; Kaya Aksoy G et al. 2016; Ota M et al. 2016; Shima H et al. 2018).
  • Allopurinol; clinical: acute tubulointerstitial nephritis occurs mainly in patients with pre-existing renal failure; usually combined with skin rash and elevated liver values, sometimes with DRESS (drug reaction with eosinophilia and systemic symptoms)

Infections: Infectious acute tubulo-interstitial nephritis (in 20% of cases): often streptococci.

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About 2-3 % of all kidney biopsies; about 7-15 % of all cases of acute kidney failure.

Drug-induced acute tubulointerstitial nephritis is one of the most common causes of acute renal failure in childhood (Kaya Aksoy G et al. 2016).

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Pathogenetically, in most cases there is a dose-independent, T-cell-mediated hypersensitivity reaction(type IV allergy) to antigens, mainly drugs (70% of cases), more rarely also infectious triggers: bacteria, viruses, protozoa etc. (Valluri A et al. 2015).

Drug-induced acute tubulointerstitial nephritis occurs independently of the dose, often as a nephrogenic organ manifestation of a generalised allergic event.

Furthermore, TIN occurs in systemic autoimmune diseases such as Sjögren's syndrome, systemic lupus erythematosus, Goodpasture's syndrome, IgA nephritis (Shima H et al. 2018) or as TINU (acute (tubulointerstitial) nephritis with uveitis (Ariba YB et al. 2017).

The cause cannot always be determined.

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Age or gender are not important for the manifestation of the disease. In a larger study the mean age of onset of the disease was 36.41 ± 17.40 years (Naqvi R et al. 2016).

Clinical features
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The clinical picture is characterized by the following symptoms:

Occurrence of oliguric (60%) or non-liguric (40%) acute renal failure after exposure to antigen.

The characteristic clinical triad can be observed in >50% of patients (Valluri A et al. 2015):

  • maculopapular exanthema (<50% of cases)
  • fever (75%)
  • eosinophilia (80%)

Arthralgias are rarer. Flank pain often occurs (due to stretching of the kidney capsule)

The symptoms may be subclinical or absent. However, their absence (often in NSAIDs as a triggering agent) does not exclude the diagnosis.

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Sonographically, the kidneys in acute interstitial nephritis appear normal in size or slightly enlarged, sometimes with an unspecific, inhomogeneously enhanced cortical echogenicity.

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Mild (tubular) proteinuria in >75% of patients (mostly significantly <1g/24 h), often microhematuria, in rare cases also macrohematuria. Proteinuria >3g,0/ 24 h indicates additional glomerular damage and is typical of NSAID-induced acute tubulointerstitial nephritis. In drug-induced TIN, frequent occurrence of eosinophilic granulocytes in the urine (this finding is considered positive if >1% of all detectable leukocytes in the urine consist of eosinophilic leukocytes).

Note: Urinary eosinophilia may also be present in pyelonephritis, prostatitis, cystitis, cholesterol emboli, or rapid progressive glomerulonephritis. Tubular defects (e.g. Fanconi syndrome) and renal tubular acidosis are rare in TIN, but common in chronic interstitial nephropathies.

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Histologically an interstitial edema and an interstitial, lymphocyte-rich, eosinophilic cell infiltrate with tubulitis are found. Immunohistologically no specific deposits are detectable.

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The suspected diagnosis of "TIN" can often be made by taking a detailed medical history. Furthermore, typical clinical triad. A kidney biopsy is often required to establish the exact diagnosis.

Differential diagnosis
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Chronically toxic, dose-dependent TIN (analgesic nephropathy e.g. caused by phenacetin, paracetamol)

Acutely toxic, dose-dependent TIN (aminoglycosides, cephalosporins, gyrase inhibitors)

Rare: There are two similar severe systemic clinical pictures with haemorrhagic fever, in which excrements of rodents (e.g. mice, rats) are ingested via the airways:

  • The hantavirus infection with the virus type Puumala is not uncommon in Germany. It is accompanied by fever, headache, drowsiness, nausea, vomiting, abdominal pain and thrombocytopenia. The associated kidney failure is characterized by interstitial inflammatory infiltrates and bleeding. The diagnosis is made serologically by antibody detection (Mantula PS et al. 2017).
  • Leptospires (spirochetosis) invading via the skin or mucous membranes of humans cause fever, myalgia, arthralgia and headache mark the first peak of the disease - followed by icterus, an increase in transaminases and renal failure mostly at the bottom of a TIN. The diagnosis is usually serological.

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Stopping the triggering medication (it is not always possible to identify it) or eliminating another triggering cause or underlying disease.

Often, however, acute kidney failure (in various studies > 70% of cases) must be treated by haemodialysis (peritoneal dialysis) (Naqvi R et al. 2016). As a drug therapy, prednisone can be administered for immunosuppression in a dose of 1 mg/kg bw/day for 14 days; slow release for 1 month is recommended. However, the effectiveness of this therapy remains questionable (Valluri A et al. 2015).

The immediate use of prednisolone is suggested in patients already on dialysis, in those with a course of renal failure lasting several weeks and in cases of severe interstitial changes in the biopsy.

If there is no response to cortisone, a therapy trial with mycophenolate mofetil is possible (data availability for this therapy option is poor).

In the case of infection-associated forms, the underlying infection must be treated. A therapy with corticoids is not indicated.

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In 60-70% of the cases after an average of 4 - 6 weeks normalization of renal function parameters (Naqvi R et al. 2016). In 30-40% of cases, the retention values remain permanently elevated. This finding manifests the transition to chronic interstitial nephritis.

Risk factors for this are, among other things, a late diagnosis, recurrent episodes and the concomitant use of analgesics or (less frequently) of herbs containing aristolochic acid (Chinese Herbs Nephropathy / Balkan nephritis). If the clinical symptoms are very acute, the diagnosis is usually made earlier, which significantly improves the prognosis.

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Drug-induced dose-independent interstitial nephritis must be distinguished from dose-dependent toxic tubule damage caused by aminoglycoside antibiotics or amphotericin B.

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Last updated on: 02.02.2021