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Acute interstitial nephritis 

Acute interstitial nephritis
Chapter:
Acute interstitial nephritis
Author(s):

Simon D Roger

DOI:
10.1093/med/9780199204854.003.210901_update_002

Update:

Substantial updates throughout chapter

Inclusion of a new figure showing granuloma in AIN

New section on likely developments of the next 5-10 years

Updated further reading

Updated on 22 September 2016. The previous version of this content can be found here.
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Essentials

Acute interstitial nephritis (AIN) is inflammation of the tubules and interstitium within the kidney, associated with a relatively sudden onset and a rapid decline in renal function. It is usually secondary to drugs [antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors being most commonly incriminated], with other causes being infections (classically streptococcal, but this is now less common) and immune disorders (systemic lupus erythematosus, sarcoidosis, and tubulointerstitial nephritis with uveitis).

Clinical features—the diagnosis of AIN should be considered in any patient with unexplained acute renal failure. Drug-induced AIN may present with a classic allergic response, including arthralgias, fever, rash, loin pain, and eosinophilia/eosinophiluria, but these are not invariable and their absence does not exclude the diagnosis. The urine typically shows low-grade proteinuria (<1 g/day). Renal biopsy is the only way to confirm or exclude the diagnosis.

Management and prognosis—treatment is by ceasing the offending agent, treating the concurrent infectious cause, or managing the immune aetiology with steroids (typically prednisolone 1 mg/kg/day, tapered to zero over 6–8 weeks). Most patients with drug-induced AIN recover renal function, but some are left with chronic renal impairment and a small proportion progress to endstage chronic kidney disease.

Introduction

Acute interstitial nephritis (AIN) is characterized by an interstitial infiltrate of inflammatory cells with relative sparing of the glomeruli and vessels, and presents as acute impairment of renal function. The term ‘tubulointerstitial’ nephritis is also applied, reflecting the damage that occurs to the tubular cells in addition to the interstitial changes.

Historical perspective

In 1898 Councilman described the first accounts of acute tubulointerstitial nephritis involving patients with scarlet fever or diphtheria, whose kidneys were sterile but had inflammatory infiltrates. Since then, drug-induced AIN has surpassed infection as a more common cause of the condition in adults, especially with the widespread use of antibiotics and proton pump inhibitors (PPIs).

Aetiology, pathogenesis, and pathology

The aetiology is divided into groups such as drugs, infections, and immune-based causes (Box 21.9.1.1).

Adapted from Droz D, Chauveau D (2003). Acute interstitial nephritis. In: Warrell DA, et al, (eds). Oxford Textbook of Medicine, pp35. Oxford University Press, UK.

Drugs

Medications are now responsible for 70 - 90% of cases of AIN. It is important to remember that any drug can cause this condition, especially with the flood of new agents entering the formulary.

The commonly recognized drugs implicated in causing AIN include PPIs, non-steroidal anti-inflammatory drugs (NSAIDs), penicillins, cephalosporins, sulfa-based agents, and frusemide (furosemide). Unexpected culprits include cocaine and Chinese herbal agents.

The PPIs have been recognized as causing AIN since 1992. They have been shown to induce AIN on rechallenge, behave as a class effect rather than due to specific drugs within the group, and are now the commonest cause of drug-induced AIN.

Infections

Many pathogenic organisms (bacterial, viral, protozoal, and fungal) have been implicated as causing AIN, and in children infection remains the commonest cause of this condition:

  • Streptococcal—what was a very common aetiology has now waned with the advent and widespread use of antibiotics.

  • Legionella—although a relatively rare cause of AIN, the organism can be detected in renal tissue by immunofluorescence and electron microscopy. Coexistent rhabdomyolysis may be present.

  • Human immunodeficiency virus—AIN is present in up to 40% of autopsy series. HIV can also cause glomerulonephritis in addition to a mononuclear cell infiltrate of predominantly CD8+ lymphocytes.

  • Epstein–Barr virus—renal involvement is not uncommon. CD8+ T lymphocytes may predominate.

  • Cytomegalovirus—more common in immunosuppressed patients (HIV-positive or transplant recipients). Irreversible renal failure may ensue.

  • Polyomavirus (BK)—the renal transplant population are more specifically at risk of BK virus inducing AIN and acute cellular rejection. This polyomavirus is present in the urothelium of 60–80% of people, with immunosuppression allowing it to become a significant pathogen in the renal transplant, resulting in BK virus-associated nephropathy (BKVAN). Management generally involves reduction in immunosuppression, with use of ciprofloxacin, cidofovir, and leflunomide also advocated (but without convincing evidence of efficacy).

  • Toxoplasmosis—AIN is uncommon but can occur as part of systemic infection.

  • Leishmaniasis—disseminated leishmaniasis (kala-azar) can present with acute kidney injury from AIN. It tends to resolve.

  • Mycobacterium—these have been recognized as inducing AIN and, along with toxoplasmosis and leishmaniasis, are a commoner cause of AIN than drug-induced cases in developing countries.

In septicaemia, bacteria such as Escherichia coli and staphylococci and fungal elements such as Candida albicans can directly invade the renal parenchyma and lead to the development of microabscesses, which are found on diagnostic renal biopsy.

Immune

  • Systemic lupus erythematosus—lupus is associated with deposition of immunoglobulins and complement. Deposits may be extensive and widespread. Cellular infiltrates include mononuclear cells, but also on occasion neutrophils. Although the tubulointerstitial infiltrate usually coexists with significant glomerulonephritis, it has been found in isolation.

  • Sjögren’s syndrome—may be associated with renal tubular acidosis. IgG and C3 may be detected on immunofluorescence staining on the tubular basement membrane.

  • Sarcoidosis—can be coupled with the formation of typical granulomas in the interstitium. Associated hypercalcaemia and cellular infiltrate may lead to dialysis-dependent renal failure.

  • IgG4-related kidney disease—lymphoplasmacytic cell-rich tubulointerstitial nephritis occurs with increased IgG4-positive plasma cells and storiform fibrosis. It can be associated with type 1 autoimmune pancreatitis, but is now considered to encompass various multi-organ inflammatory conditions.

  • Tubulointerstitial nephritis with uveitis (TINU) syndrome—described by Dobrin in 1975, uveitis may precede or follow the renal dysfunction. Autoimmune pathogenesis is suspected, with a strong association with specific human leucocyte antigens (HLA) (DQA1*01/DQB1*05/DRB1*01). This commonly affects pubertal females and responds to oral steroids, but is prone to relapse.

Anti-tubular basement membrane antibodies have been reported in rare idiopathic forms.

A variety of primary glomerulonephritides may cause a secondary tubulointerstitial inflammation and nephritis, e.g. in the context of anti-glomerular basement membrane antibodies and coexistent anti-tubular basement membrane antibodies (occurring in 50%), or membranous glomerulonephritis.

Pathogenesis

AIN is characterized by tubulitis with a heavy cellular infiltrate. Renal dendritic cells commence a process that results in interstitial fibroblastic cells expressing a variety of growth factors and cytokines such as transforming grown factor-beta (TGF-β‎) and platelet-derived growth factor, which leads to inflammatory cascades and subsequent production of extracellular matrix proteins (collagens, fibronectin, laminin) and fibrotic change. This results in tubular destruction and the development of glomerular sclerosis. There are conflicting views on the role of fibroblasts derived from epithelial-to-mesenchymal transition having a vital importance in tubulointerstitial fibrosis development. This process progresses to the classic pathological changes of chronic interstitial nephritis.

There are two possible mechanisms by which AIN develops:

  • Antigen-driven immunogenicity

AIN is classically associated with an infiltrate of T lymphocytes (both helper-inducer and suppressor-cytotoxic). This leads to T cell-mediated hypersensitivity and cytotoxic T cell injury. The presence of CD4 helper T cells at the site of injury indicates immune activation. Th1 helper cells [releasing tumour necrosis factor-beta (TNF-β‎) and interferon-gamma (IFN-γ‎)] favour delayed-type hypersensitivity responses and the production of CD8 cytotoxic lymphocytes, and Th2 cells [releasing interleukin (IL)-5 and IL-4] attract eosinophils and help B cells form plasma cells that secrete antibodies. The presence of TGF-β‎1 acts as a proinflammatory molecule and is the most important profibrotic factor. In PPI-induced AIN, CD4+ lymphocytic aggregates combined with co-staining of CD4 IL and 17A/F suggest a Th17-mediated inflammatory process. The presence of T-bet+ cell infiltrates point to additional Th1 involvement.

  • Humoral immunogenicity

Although T cells are the main villain implicated in pathogenesis, there is also evidence in experimental animal models to implicate a role for the humoral immune system. This involves tubular basement membrane antibodies and complement. This process is active in the TINU syndrome when there is an increase in IgG reactive against a 125-kDa kidney protein.

The exact pathogenesis of drug-induced AIN is yet to be elucidated. It is thought that the drug or its metabolites either act as haptens (mimicking renal antigens) or deposit as circulating immune complexes. This is believed to stimulate a T cell hypersensitivity reaction. Evidence for this theory is derived, in part, because of the extrarenal manifestation of hypersensitivity (rash, arthralgias, and eosinophilia).

Pathology

On light microscopy the renal biopsy typically shows an infiltrate within the interstitium of T lymphocytes (especially CD4+ and CD8+ cells), monocytes, macrophages (expressing CD14+ and CD68+ in addition to cell activation markers), and possibly polyclonal plasma cells and eosinophils (Fig. 21.9.1.1). The infiltrate may vary in intensity. There may be extensive interstitial oedema. If granulomas have formed, then the differential includes a drug reaction, sarcoidosis, tuberculosis, or acute bacterial infections (Fig. 21.9.1.2). Fibrosis within the interstitium has been detected within 2 weeks, as a component of the reparative process. The tubules themselves may show necrosis or signs of regeneration.


Fig. 21.9.1.1 Renal biopsy (haematoxylin and eosin stain), demonstrating AIN with cellular infiltrate and sloughing of tubular epithelial cells.

Fig. 21.9.1.1
Renal biopsy (haematoxylin and eosin stain), demonstrating AIN with cellular infiltrate and sloughing of tubular epithelial cells.

In primary AIN, when the sample is examined by light microscopy or immunofluorescent techniques, the glomeruli and vessels are either unremarkable or show only minor change. Immunofluorescence of the tubules and interstitium may stain positive for anti-tubular basement membrane antibodies, IgG, and IgM in addition to fibrinogen. Linear IgG and C3 deposition is rarely found, although it has been associated with antibiotic-induced disease (β‎-lactams and ciprofloxacin). Electron microscopy reveals altered continuity of the tubular basement membrane.

Fibrosis within the interstitium has been detected within 2 weeks as a component of the reparative process.

Epidemiology

AIN is not a common entity, being found in 1–3% of unselected renal biopsy series. Its exact incidence is difficult to gauge as renal physicians apply different criteria for performing diagnostic renal biopsies. However, most series suggest 15–27% of kidney biopsies performed for investigation of acute kidney injury demonstrate AIN, the higher percentage being reported where the cause of acute kidney injury is unknown and in the presence of inactive urinary sediment (i.e. lack of heavy proteinuria, lack of significant haematuria, or lack of the presence of dysmorphic red blood cells). The prevalence of AIN may be increasing, especially in the elderly, possibly reflecting more diagnostic kidney biopsies or increased incidence of drug-induced AIN.

Clinical features

The clinician should always consider AIN in any patient with unexplained acute kidney injury, with or without specific tubular dysfunction. It is also important to consider AIN in a patient with chronic kidney disease whose renal function suddenly deteriorates at a rapid rate. A thorough drug history is essential, including over-the-counter medications, herbal compounds, and other non-prescription agents, and the dates/duration of exposure. Given that drug-induced AIN is an idiosyncratic reaction, it must be presumed that all drugs might be causative.

Drug-induced AIN may present with a classic allergic response, including fever, rash, arthralgias, and eosinophilia/eosinophiluria. The recognized clinical pattern of drug-induced AIN has changed since the disappearance of the classic methicillin-induced damage. These systemic features may present early (days to weeks after drug exposure) or up to a mean of 3 months following drugs such as PPIs. With drugs such as NSAIDs, it can occur up to years later. In patients who are surreptitiously rechallenged with an offending drug, the onset of AIN is rapid. The development of AIN is not dose-related (Table 21.9.1.1)

Table 21.9.1.1 Clinical features of AIN (data pooled from several studies)

Acute kidney injury

100%

Acute kidney injury requiring renal replacement therapy

40%

Arthralgia

45%

Rash

18%

Fever

32%

‘Allergic triad’ (fever, rash, and arthralgia)

10%

Eosinophilia

31%

Non-visible haematuria

67%

Visible haematuria

5%

Leucocyturia

82%

Non-nephrotic-range proteinuria

93%

Nephrotic-range proteinuria

2.5%

Nephrotic syndrome

0.8%

PPIs, NSAIDs, and β‎-lactam antibiotics are the most commonly found causes of iatrogenic AIN.

Proton pump inhibitors

PPIs are one of the most widely prescribed classes of drugs in the Western world. All five drugs in the class have been reported as causative agents. The triad of fever, rash, and eosinophilia associated with classical methicillin-induced AIN is less prominent or even absent in PPI-induced AIN. The presenting complaints are nonspecific in nature, including tiredness, nausea, and weight loss. The commonest abnormalities on investigation, apart from raised serum creatinine, are low-level proteinuria, pyuria, and eosinophiluria.

Due to the widespread availability of these drugs, both over-the-counter in some countries and on prescription, there is a high risk of inadvertent rechallenge unless patients are clearly counselled. This iatrogenic complication may be devastating, hence education of all prescribing doctors (including general practitioners, gastroenterologists, and surgeons) in addition to pharmacists is warranted.

NSAIDs

This class of drugs [including selective cyclo-oxygenase (COX)-2 inhibitors] rarely causes extrarenal manifestation, but concurrent nephrotic syndrome with heavy proteinuria and oedema is common, being present in up to 70% of cases. Macroscopic haematuria is rare. In Europe, fenoprofen accounts for up to 50% of cases. Precise history-taking is imperative because these medications are readily available over the counter and are usually taken on an ‘as-needed’ basis, and many patients may not regard them as ‘drugs’ unless specifically asked about them by the clinician.

β‎-lactam antibiotics

These agents cause the ‘classic’ allergic drug-induced AIN. Occurring within a few days or up to 2 months after starting treatment, fever, skin rash, arthralgias, eosinophilia, and renal impairment are evident.

Other drugs of note

The use of herbal medicines has increased in developed countries; these are often incorrectly believed by patients to be innocuous, but they can cause AIN. Cocaine abuse can result in AIN, also in acute kidney injury from rhabdomyolysis and arterial hypertension induced by intense vasoconstriction. Deferasirox (oral iron chelator), pamidronate, amlodipine, and tyrosine kinase inhibitors (which more commonly produce nephrotic-range proteinuria and hypertension) can cause acute kidney injury due to AIN.

Differential diagnosis

The differential diagnosis includes other causes of renal impairment. The differentiation of acute tubular necrosis from AIN may be difficult. In this situation renal biopsy is required to conclusively confirm or dismiss a provisional diagnosis.

In contrast, glomerulonephritis generally presents with significant proteinuria (>1/day; urinary ACR >60 mg/mmol; urinary PCR >100 mg/mmol), in addition to dysmorphic red cells and granular/cellular casts on freshly spun urine microscopy.

When assessing kidney biopsy specimens, the infiltrate of mononuclear cells needs to be differentiated from a monoclonal infiltrate, which would be found in renal lymphoma or leukaemia.

Clinical investigation

Laboratory testing demonstrates an elevated urea and creatinine. There may be associated biochemical changes reflecting tubular dysfunction such as hypo- or hyperkalaemia, aminoaciduria, glycosuria, uricosuria, or alterations in serum bicarbonate. Either type I (distal) or type II (proximal) renal tubular acidosis patterns may predominate.

The full blood count may reveal a high eosinophil count (up to 80% in drug-induced AIN caused by β‎-lactam antibiotics, but less commonly in other drug-induced causes).

Microscope examination of the urine may demonstrate eosinophils when stained with Wright’s or Hansel’s stain. These stains are pH-dependent. Other causes of eosinophils in the urine include prostatitis, bladder carcinoma, eosinophilic cystitis, and cholesterol emboli. Eosinophils in the urine have 25−40% sensitivity, 72% specificity, and a positive predictive value of 3–30%. The use of urine eosinophils as a screening test with such poor sensitivity and low positive predictive value is not recommended; it may not provide solid evidence and may delay renal biopsy and treatment.

There may be non-specific increases in inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, and globulin concentrations. The urine typically has low-range proteinuria (<1/day; urinary ACR <60 mg/mmol; urinary PCR <100 mg/mmol).

Urinary biomarkers of acute kidney injury such as monocyte chemoattractant protein-1 and neutrophil gelatinase-associated lipocalin have been compared against renal biopsy findings in AIN but remain only an experimental tool.

Gallium scans have been assessed as another diagnostic tool in helping to differentiate AIN from acute tubular necrosis. They are positive in AIN but negative in the latter. Kidneys with AIN enhance as a result of the binding of gallium-67 to lactoferrin, which is produced, released, and found on the surface of lymphocytes within the interstitium. Although not giving a definitive diagnosis, it may be of assistance when renal biopsy is contraindicated or refused. Fluoro-2-deoxy-D glucose-positron emission tomography (FDG-PET) accumulates not only in cancer cells, but also in the lymphocytes, macrophages, and neutrophils of inflammatory reactions, but further assessment is required to judge the utility of this imaging modality in AIN.

Renal biopsy is the gold standard when making the diagnosis of AIN. Its primary usefulness is to confirm or exclude a diagnosis. The clinician is often faced with a patient who presents with an elevated creatinine/reduced estimated glomerular filtration rate, inactive urine sediment, and a long list of possible offender medications that may cause AIN. This means that a strong argument can be made for performing a renal biopsy in all cases of suspected AIN, with the exception being where the clinician is reasonably confident of the diagnosis and judges that biopsy in the particular patient would constitute a greater risk than that of stopping any likely offending drug and giving steroids.

Treatment

The diagnosis of drug-induced AIN is vital as prompt identification and discontinuation of the causative agent facilitate recovery of renal function.

Steroid treatment is problematic. Immediate versus delayed or no treatment with steroids may result in a lower subsequent creatinine level, with a significant correlation between the delay in steroid treatment and the final serum creatinine, but there are no randomized controlled trials, only retrospective observational data.

If steroids are prescribed, then a standard regimen would be oral prednisone at 1 mg/kg/day, tapered to zero over a 6- to 8-week period. Steroid resistance may require the addition of other immunosuppressants such as cyclophosphamide, ciclosporin, and mycophenolate. Plasma exchange has been utilized in patients testing positive for tubular basement membrane antibodies.

Supportive treatment may be required if the degree of uraemia warrants it, including renal replacement therapy with dialysis.

Prognosis

Significant recovery of renal function, with return of serum creatinine to baseline or near baseline, can be anticipated in most cases of AIN, but this does not happen in all cases, and some even progress to endstage chronic kidney disease. The prognosis depends on the severity and degree of interstitial fibrosis. Other parameters that predict a less good outcome are high initial creatinine, renal impairment that has been present for more than 3 weeks, and granulomata or more pronounced interstitial cellular infiltrates on renal biopsy. The phenotype of inflammatory cells or the degree of tubulitis has not been shown to be prognostic.

The pattern of recovery often follows two stages: a rapid improvement over 6–8 weeks and then a slower phase of improvement that may occur over the following 12 months.

Likely developments of the next 5 to 10 years

Treatment of this condition has not been subject to the rigors of a randomized controlled trial particularly looking at the benefits of corticosteroids. Because of the low incidence of this entity, a multicentre study would be required. This is unlikely to occur without a concerted effort from a national clinical trials network. Future studies will be required to ascertain whether there are any epidemiologic factors in patients that can predispose them to AIN.

Further reading

Bagnis CI (2004). Herbs and the kidney. Kidney Int, 44, 1–11.Find this resource:

    Clarkson MR, et al. (2004). Acute interstitial nephritis: clinical features and response to corticosteroid therapy. Nephrol Dial Transplant, 19, 2778–83.Find this resource:

    Councilman WT (1893). Acute interstitial nephritis. J Exp Med, 3, 393–420.Find this resource:

      Dobrin RS, Vernier RL, Fish AL (1975). Acute eosinophilic interstitial nephritis and renal failure with bone marrow lymph node granulomas and anterior uveitis: a new syndrome. Am J Med, 59, 325–33.Find this resource:

      Geevasinga N, et al. (2006). Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol, 4, 597–604.Find this resource:

      González E, et al. (2008). Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int, 73, 940–6.Find this resource:

      Raghavan R, Eknoyan G (2014). Acute interstitial nephritis—a reappraisal and update. Clin Nephrol, 82, 149–62.Find this resource:

      Randhawa P, Brennan DC (2006). BK virus infection in transplant recipients: an overview and update. Am J Transplant, 6, 2000–5.Find this resource:

      Rossert J (2001). Drug-induced acute interstitial nephritis. Kidney Int, 60, 804-17.Find this resource:

      Ruffing KA, et al. (1994). Eosinophils in urine revisited. Clin Nephrol, 41, 163–6.Find this resource: