1. What is acute tubulointerstitial nephritis?

Acute tubulointerstitial nephritis (ATIN) is characterized by inflammation and edema in the kidney tubulointerstitium and can cause acute kidney injury (AKI). Definitive diagnosis is established by kidney biopsy, though this may not be necessary if the index of suspicion for ATIN is high. A retrospective study done by Goicoechea showed that the incidence of ATIN, particularly ATIN in the elderly, has increased over the past decade due to a higher biopsy rate and/or an increased use of causative drugs, such as nonsteroidal antiinflammatory drugs (NSAIDs) and antibiotics.

2. What are the most common causes of ATIN?

The most common causes of ATIN are classified as below:

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  Drugs

  
  
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  Infection

  
  
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  Autoimmune systemic diseases

  
  
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  Idiopathic

Drugs account for most ATIN cases. Drug-induced ATIN is not dose dependent, but rather is an idiosyncratic reaction. Repeat exposure to the same drug or a closely related agent can lead to recurrence of the disease process ( Table 45.1 ).

3. Describe the pathogenesis of ATIN.

ATIN is caused by an immune reaction in the kidney. Drug-induced ATIN is caused by a cell-mediated, delayed-hypersensitivity type of immune response characterized by infiltration of CD4+ T cells. In addition, an antibody-mediated response may play a role given high serum immunoglobulin (Ig)E levels and, rarely, anti–tubular basement membrane (anti-TBM) staining on kidney biopsy.

4. What are the characteristic histopathologic findings in ATIN?

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  Presence of an inflammatory cell infiltrate in the interstitium

  
  
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  Interstitial edema

  
  
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  Tubulitis

  
  
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  Other findings may include:

  
  
  
  
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    Granulomas in the interstitium. As seen in sarcoidosis, Sjögrens, and tubulointerstitial nephritis and uveitis (TINU)

    
    
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    Anti-TBM antibodies

    
    
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    Diffuse foot process effacement. As seen in NSAID-induced minimal change disease.

  
  
  
  
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  Normal glomeruli and vessels. This, in particular, distinguishes tubulointerstitial nephritis from inflammatory glomerular diseases (e.g., glomerulonephritides)

5. What are the clinical manifestations of ATIN?

ATIN may be asymptomatic, but in some patients it presents with fatigue, fever, nausea, vomiting, rash, or arthralgias. The classic triad of fever, maculopapular rash, and peripheral eosinophilia that was originally described with methicillin-induced ATIN is seen in less than 10% of ATIN cases.

6. What are the laboratory manifestations of ATIN?

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  Azotemia (elevated blood urea nitrogen and serum creatinine)

  
  
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  Peripheral eosinophilia

  
  
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  Eosinophiluria

  
  
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  Sterile pyuria (occasionally, white blood cell [WBC] casts)

  
  
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  Microscopic hematuria (very rarely, red blood cell [RBC] casts)

  
  
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  Proteinuria (usually <3.5 g/day, with the exception of NSAID-induced ATIN)

  
  
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  Renal tubular acidosis (RTA; varies depending on which segment of the renal tubule is affected)

Wu et al. investigated the use of urine biomarkers in the evaluation of drug-induced ATIN and found that urinary monocyte chemotactic peptide-1 (MCP-1) levels showed the closest correlations with interstitial inflammation when compared to other urine biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), a1-microglobulin (a1-MG), and N-acetyl-B-D-glucosaminidase (NAG).

7. What is the importance of eosinophiluria in ATIN?

Eosinophiluria is a nonspecific finding that can be seen in a variety of conditions (e.g., acute pyelonephritis, acute glomerulonephritis, acute cystitis, and prostatitis). Muriithi et al. found that even at a 5% cut-off, urine eosinophils are poorly discriminated between ATIN and other forms of kidney disease.

8. What drugs cause ATIN?

The three most common drug classes that cause ATIN are: NSAIDs, proton-pump inhibitors, and antibiotics. Different drug classes are associated with different manifestations of ATIN. For example, while beta-lactam antibiotics may be associated with a systemic allergic response (fever, rash, and/or peripheral eosinophilia), NSAID-induced ATIN is not typically associated with extrarenal symptoms. ATIN secondary to NSAIDs may manifest 6 to 18 months after initiation of the medication. A large percentage of patients with NSAID-induced ATIN have nephrotic syndrome. Withdrawal of NSAIDs leads to recovery in most cases, though recovery may take up to 12 months.

9. Which autoimmune diseases are associated with ATIN?

Lupus nephritis, sarcoidosis, Sjögren disease, ANCA-associated vasculitis, and Crohn disease. See more on this in the section “Chronic tubulointerstitial disease” below.

10. What is the role of gallium scanning in the diagnosis of ATIN?

The presence of an active interstitial inflammatory infiltrate in ATIN leads to a diffuse, intense kidney uptake of the gallium67 radioisotope. This finding is nonspecific and can be seen in many causes of AKI. Note that acute tubular necrosis (ATN) is characterized by decreased uptake of gallium67, thus the gallium scan may be useful in distinguishing ATIN from ATN.

11. What is the most definitive means to diagnose ATIN?

Definitive diagnosis is made by kidney biopsy. Because it is common practice to withdraw the suspected etiologic agent and carefully observe the kidney function in the ensuing days, kidney biopsies are not always performed in suspected cases of ATIN.

The most common indications for doing a kidney biopsy in suspected ATIN are as follows:

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  Unexplained AKI

  
  
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  Absence of improvement after withdrawal of suspected offending agent

  
  
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  Consideration of immunosuppression for treatment of suspected ATIN

12. What are the treatment options for ATIN?

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  Withdrawal of offending agent

  
  
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  Corticosteroid therapy

  
  
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  Steroid-sparing immunosuppressive therapy

To date, the optimal treatment for ATIN is unclear. There have been no randomized, controlled trials investigating the use of immunosuppressive therapy for treatment of ATIN.

Corticosteroids may be considered in patients with biopsy-proven ATIN in whom there is prolonged and/or progressive kidney dysfunction despite withdrawal of the offending agent. There is no standardized treatment regimen for ATIN. Typically oral prednisone is started at 1 mg/kg per day and tapered off over 8 to 12 weeks.

Preddie et al. reported the use of mycophenolate mofetil (MMF) for 13 to 34 months in a group of patients who were steroid dependent for up to 6 months.

For now, one may consider the use of MMF for those who have biopsy-proven ATIN, who are either intolerant of, dependent on, or resistant to corticosteroids.

13. What is the typical course of ATIN?

The majority of suspected cases of ATIN, whether treated by withdrawal of the suspected offending agent alone or with immunosuppression, result in the recovery of kidney function in a few days to weeks. Prolonged kidney dysfunction (>3 weeks) and the presence of interstitial fibrosis and tubular atrophy on histopathology are considered poor prognostic features.

14. What is chronic tubulointerstitial nephritis?

Chronic tubulointerstitial nephritis is characterized by the presence of chronic interstitial inflammation, interstitial fibrosis, and tubular atrophy, which leads to chronic kidney disease (CKD). Causes of chronic tubulointerstitial nephritis are listed in Box 45.1 .

Different diseases affect different segments of the tubule. The functional abnormalities depend on the tubular site of involvement. For example, Sjögrens leads to distal tubular injury and is associated with metabolic acidosis (type 1 RTA) and hypokalemia. Injury involving the kidney medulla is characterized by impaired ability to concentrate urine, as seen in sickle cell nephropathy ( Box 45.2 ).

Box 45.2.

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