Introduction

More than 95% of the kidney is made of interstitium and tubules, suggesting the importance of a better understanding of tubulointerstitial nephritis (TIN). TIN is a primary injury to renal tubules and interstitium, resulting in decreased renal function. The acute form is most often due to allergic drug reactions or to infections. The chronic form has diverse causes including genetic, metabolic and environmental toxins and herbs. Previously, infections used to be the primary causes of TIN, but recently an immuno-allergic mechanism due to drugs such as antibiotics, non-steroidal anti-inflammatory drugs (NSAID) and many others, seems to be the predominating cause [1]. Identification of the aetiology is of importance in order to eliminate and prevent the responsible causes in the future. TIN represents 3–7% of acute kidney injury detected on kidney biopsy [2, 3] in children, whereas it may reach 27% in adults [4].

Definition

Acute TIN is an immune-mediated cause of acute renal failure (ARF) characterised by the presence of inflammatory cell infiltrate in the interstitium of the kidney (Fig. 1) [5, 6]. The term TIN was initially described by Councilman in 1898 when he observed histological changes in patients infected with diphtheria and scarlatina. The disease is characterised histologically by inflammation (monocyte/lymphocyte infiltrate) and local oedema that involves mainly the tubules and interstitial tissue. The manifestation of the disease is either of sudden onset or, rarely, chronic with slow evolution leading to end-stage renal disease (Table 1).

Fig. 1
figure 1

Acute interstitial nephritis. Interstitial lymphocyte and mononuclear cell infiltrate. Normal glomeruli. Dilation of peritubular capillaries. Original magnification × 400

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Table 1 Acute interstitial nephritis
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Aetiology

According to the aetiology, TIN can be classified into two main types: non-infectious and infectious [7, 8]. Concerning the non-infectious causes, the use of certain drugs (Table 2) is either directly responsible for TIN or indirectly by creating a hypersensitivity reaction, mainly after the use of NSAID [9]. Usually there is a free period between the use of medications and the onset of TIN. Such a period varies from 5 days up to 5 weeks. Several reports have suggested qualitative differences in NSAID-induced TIN as opposed to TIN secondary to other pharmacological agents. NSAID-induced TIN seems to be less severe compared with other drug-induced TIN, most probably because the anti-inflammatory properties of NSAID limit the TIN activity [10]. These differences have been stated to include less proteinuria, absence of systemic eosinophilia and less eosinophilic infiltrate on biopsy and a better clinical outcome [10, 11]. The identification of a certain medication that leads to TIN is considered as an absolute contraindication to its reuse. Intravenous immunoglobulin infusions have rarely been reported to cause TIN [12]. Another rare non-infectious cause is related to neoplasia [13]. Chlorellae are fresh water unicellular microscopic algae, widely used as a food supplement in Japan. It has been shown recently that ingestion of chlorellae tablets may lead to acute TIN [14].

Table 2 Medications frequently associated with acute tubulointerstitial nephritis
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Viral (CMV, hepatitis, HIV, EBV, Hantavirus, Polyomavirus etc.), bacterial (salmonella, streptococcus, yersinia, brucella), fungal (histoplasmosis) and parasitic (Leishmania, Toxoplasma) infections are described to be responsible for TIN. HIV-infected patients develop a unique form of acute interstitial nephritis secondary to diffuse infiltrative lymphocytosis syndrome [15]. One particular form of TIN is found in Leptospirosis. Leptospira outer membrane proteins may induce tubular injury and inflammation through the Toll-like receptors-dependent pathway followed by activation of nuclear transcription factor kappa B [16].

Acute pyelonephritis is a separate subgroup of TIN as the mechanism is due to parenchyma infection and must therefore be considered as a localized TIN. Only in the case of aggravating situations such as urinary tract obstruction or high-grade vesico-renal reflux is a development towards chronic TIN rarely observed.

Some cases of AIN are secondary to diseases with immune-mediated mechanisms such as lupus, Sjögren’s disease or tubulointerstitial nephritis with C3 and IgG deposits in the tubular basement membrane (TBM).

Chronic TIN might occur after a systemic disease that causes immunity disequilibrium such as sarcoidosis, lupus, Sjögren’s syndrome, vasculitis, Crohn’s disease [17], but also in the case of obstructive uropathy. Classifying patients with lupus nephritis was based on glomerular lesions. Recent studies have suggested that the extent of tubulointerstitial lesions may be helpful in predicting renal outcome in patients with lupus nephritis [18].

Pathophysiology

Tubulointerstitial nephritis is characterised by infiltration of inflammatory cells in the renal interstitium associated with local oedema with or without fibrosis [5]. Such inflammation does not involve the renal vessels or the glomeruli. Fibrosis is usually absent initially, but may occur over time, especially if treatment is delayed. The inflammatory cells are mainly T-lymphocytes and mononuclear cells with eosinophils that might lead to eosinophilic microabscesses. In chronic tubulointerstitial nephritis, the inflammatory cells are progressively replaced by fibrosis. Histologically, there is an increase in the interstitial tissue with fibrosis and cellular infiltrates: fibroblasts, T-lymphocytes, and macrophages. Rarely, presence of plasma cells, neutrophils or eosinophils is observed. Cytotoxic lymphocytes CD8+ are the main lymphocytes that cross the basal tubule. Monocytes and macrophages increase the production of the adhesive molecule (particularly the osteopontin) that leads to fibrosis. In the atrophied tubules the epithelial cells are flattened with thickening of the basal membrane. The aetiology of the acute and chronic TIN seems to be similar. It seems that some cases of acute TIN might become chronic in the absence of early and adequate treatment. Moreover, both nephronophthisis and obstructive uropathy are significant causes of chronic TIN. Other granulomatous diseases can be involved in chronic TIN, like salmonella [19] or BK virus in the case of immunodeficiency, brucella and histoplasmosis [20].

The pathophysiological mechanisms in the acute and chronic forms may involve renal hypoperfusion with functional renal insufficiency. Other mechanisms are either due to direct tubular toxicity (contrast medium injection, cyclosporine, etc.) [21, 22] and indirect mechanisms like rhabdomyolysis and crystalluria. Other possible mechanisms are intratubular obstruction–mainly due to renal elimination of drugs that are non-soluble, leading to intratubular precipitation (methotrexate, indinavir, etc.) [12, 23, 24].

Drug-induced kidney injury is related to hypersensitivity. Such an immuno-allergic lesion is not related to the dosage of the drug used. In the case of systematic infection, the interstitial lesion can be due to the infection itself or to the drug used for treatment, for example HIV or toxoplasmosis, which might lead to direct kidney injury or to immuno-allergic reaction to anti-retroviral drugs like Indinavir [24, 25] or sulfadiazine.

Pathogenesis

There is a high probability that AIN is due to immuno-allergic disequilibrium, mainly cell-mediated immunity [26], but the exact mechanism is still unknown. The presence of T helper lymphocytes and T suppressor among the cellular infiltrates suggest that such cells play a role in the pathogenesis of TIN. In certain cases humoral mechanisms are involved due to the presence of protein complement, immunoglobulin, and antibodies against tubular membrane found in the interstitium [5].

Pathogenesis of drug-induced TIN is believed to have an immunological basis, as indicated by the relatively common appearance of extrarenal manifestations of hypersensitivity and the recurrence of AIN after re-exposure to the responsible drug. Drug-derived antigens can mimic an antigen normally present within the TBM, inducing an immune response directed against this antigen (Fig. 2a). Tubular cells have the capacity to hydrolyze and process exogenous proteins. Therefore, medications or parts of it can bind to a normal component of the TBM, acting as a hapten (Fig. 2b). Medications and specific microbial antigens could elicit an immune reaction after their deposition in the interstitium (Fig. 2c) or they are deposited as immune complexes (Fig. 2d) [27].

Fig. 2
figure 2

Mechanisms of drug-induced acute interstitial nephritis (AIN). a The drug can mimic an antigen normally present within the tubular basement membrane (TBM) or the interstitium. b The drug, or part of it, can bind to a normal component of the TBM and act as a hapten. c The drug can bind to the TBM or deposit within the interstitium and act as a planted antigen. d The drug can elicit the production of antibodies and become deposited in the interstitium as circulating immune complexes [27]

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Infection-related acute TIN usually leads to a sterile infiltrate, suggesting that immunological disturbances might be responsible for TIN. Local infection may induce autoimmune response against autoantigens in the infected kidney and thereby trigger organ-specific autoimmune disease [28].

Tubulointerstitial nephritis antigen (TIN-ag), which has been localized to the renal TBM may be a target antigen in some forms of TIN [29, 30]. Recently, a case of a child with chronic renal failure and a large deletion of the gene coding for human TIN-ag was reported, suggesting that the alteration or absence of TIN-ag might cause childhood-onset chronic interstitial nephritis [31].

Cubulin and megalin are giant glycoprotein receptors on the luminal surface of the proximal tubular cells responsible for light chain endocytosis. In patients with multiple myeloma it has been found that light chains can be nephrotoxic and can produce acute proximal tubular damage or chronic tubulointerstitial nephropathy. It is not clear whether excessive light chains or anomalies of cubulin or megalin play the primary pathogenic role [32–34]. Moreover, several studies have considered a possible relation between autoantibodies against modified C-reactive protein (mCRP) and tubulointerstitial nephritis and uveitis (TINU) syndrome, concluding that mCRP might be a target autoantigen not only in TINU syndrome, but also in other chronic nephropathies [35–37].

Clinical presentation

Symptoms and signs of AIN may be non-specific and are often absent unless symptoms and signs of renal failure develop. In the majority of cases, there is a conserved urine output. Some patients even have polyuria and nocturia with signs of tubular dysfunction (i.e. a defect in urinary concentration and sodium reabsorption). Patients with allergic interstitial nephritis may demonstrate with the triad of fever, eosinophilia and allergic rash in about 20% of patients. Clarkson et al. in a large study on 2,598 patients found arthralgia in 45%, fever in 30%, skin rash in 21% and loin pain in 21% of patients. However, absence of these symptoms does not exclude AIN [27, 38].

The severity varies from a minimal increase in urea levels with abnormal urinary findings in asymptomatic patients to severe forms with acute renal failure and decreased urine output [39]. Biological investigation often detects signs of tubular dysfunction with isolated glucosuria in some patients and features of Fanconi syndrome in others [40, 41].

Eosinophils are present in 25% of patients in the urine, mainly in TIN secondary to immuno-allergic origin. Minimal proteinuria (0.3–0.5 g/24 h) of low molecular weight is frequently found. In very rare cases patients present with nephrotic syndrome. A routine urine analysis might reveal the presence of white or red blood cells. Other drug-related abnormalities may be found concomitantly, such as haemolytic anaemia and liver injury. Elevation of total IgE has been found in about 50% of cases [42]. Immunological investigation with antibodies against deoxy-ribonucleic acid and anti-nuclear and serum complement are usually normal, except in rare auto-immune disease, such as lupus interstitial nephritis [36, 43].

As for radiological findings kidney ultrasound shows either normal kidney size or moderately increased kidneys with hyperechogenicity due to infiltration with inflammatory cells [36].

As the symptoms might be present only in about 20% of cases and are usually non-specific, kidney biopsy (KB) is the only reliable method to prove the diagnosis. It usually shows eosinophilic cellular infiltration of the renal parenchyma with sparing of the glomeruli. In practice, KB is used in doubtful or severe cases with anuria or prolonged renal function impairment, or in the absence of clinical and biological findings after withdrawal of the suspected medication.

TINU syndrome

The association between TIN and uveitis was described for the first time in 1975. Initially, a female–male ratio of 3–1 has been reported, but recent data do not confirm a female predominance [44]. The TINU syndrome appears usually before the age of 20, but may occur at any age between 9 and 74 years [44]. TINU is an uncommon condition characterised by acute tubulointerstitial nephritis with favourable course and uveitis with chronic relapsing course [45, 46]. Although considered to be an unusual condition and a rare finding in patients with AIN, the prevalence of uveitis among children might reach 33% [47]. Usually, the onset of uveitis follows the onset of the interstitial nephritis, but may also occur before or concurrently. The exact pathogenesis is still unclear, but a lymphocyte-mediated immune mechanism has been suggested [48]. A familial occurrence of inherited TINU syndrome in two generations has been reported recently [49]. Moreover, the association among TIN, uveitis, and other diseases like Fanconi syndrome in a patient with ankylosing spondylitis has been reported [40]. The clinical presentation is not specific (fatigue, anorexia, fever). Abdominal pain, articular and skin rash might accompany the presenting symptoms. The ocular lesion is generally uveitis and is bilateral in 77% of cases with or without posterior uveitis [50]. The association among HLA-DQA1*01, HLA-DQB1*05, and HLADRB1*01 and TINU syndrome has been found [51, 52]. Laboratory findings might show anaemia, elevated erythrocyte sedimentation rate and haematuria associated with the anomalies usually found in AIN. However, biological investigation cannot always clearly distinguish TINU syndrome from simple AIN. Kidney histology is undistinguishable from AIN. If eosinophils are found in the infiltrate, sarcoidosis [53], Behçet disease, and systemic lupus should be considered as a differential diagnosis.

Treatment

Elimination of the suspected agent is the first step in the treatment. The main treatment of TIN is symptomatic. In the case of renal failure, maintaining the hydro-electrolytic balance is the most important consideration. There are no randomised studies that show a better disease outcome after steroid treatment [54]. In the case of severe renal failure, most paediatric teams recommend steroid treatment without waiting for spontaneous recovery [55]. While there was some variation in the dosage and length of steroid treatment, the typical regimen is intravenous methylprednisolone 1,000 mg per 1.73 m2 body surface on three consecutive days followed by oral prednisone at 2 mg/kg tapered over 3–6 weeks [56]. Several small retrospective studies have suggested that corticosteroid improves clinical outcome; however, no prospective studies exist [57, 58]. Clarkson et al. showed the absence of the role of steroids in the early recovery of TIN [38]. On the contrary, Gonzalez et al. have shown a favourable response to steroid therapy in drug-induced AIN, and early treatment initiation was considered beneficial, probably because of decreased fibrinogenesis in the interstitium [59]. Other immunosuppressive medications, such as mycophenolate mofetil (MMF), have been considered an option in patients who are steroid-resistant or steroid-dependent [60]. So far, no studies have compared the efficacy of MMF with that of steroids in patients with TIN. Further immunosuppressive drugs, such as methotrexate, cyclosporin A and azathioprine [61] have been used in the treatment of TIN and TINU syndrome, but more studies are needed to confirm their efficacy. DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) presents several similarities to AIN. Cyclophosphamide and cyclosporine A were correlated with rapid clinical improvement in isolated reports on patients with DRESS syndrome [62]. Therefore, cyclophosphamide might be discussed in patients with steroid-resistant forms, even if proof of efficacy has not yet been obtained. TNF-alpha inhibitors are also used in the treatment of uveitis; the efficacy of infliximab has been reported to be superior to that of etanercept [63].

Prognosis

In the majority of children with acute TIN the outcome seems to be excellent [3, 29, 64]. Kidney function is usually restored within several weeks. The indication for kidney biopsy is mainly severe renal failure with or without oliguria and for others the need for dialysis [3]. Histological signs that might indicate bad prognosis are diffused inflammation, excessive neutrophils infiltration (1–6%), and the presence of interstitial fibrosis. A study by Schwarz et al. found that clinical markers of chronicity were subacute symptoms, a prolonged intake of the suspect drug, and a chronic analgesic or NSAID; histological predictors of chronicity were tubular atrophy, interstitial granuloma, or pronounced interstitial cell infiltration on kidney biopsy [65]. Further, fibrosis on initial biopsy was shown to be a predictive marker for chronic renal failure; however, tubulitis had no prognostic value [66]. One particularity of TINU syndrome is that uveitis might become chronic, requiring long-term follow-up with regular ophthalmological examination, even in the absence of renal fibrosis [44]. For clinical symptoms, laboratory tests including plasma creatinine, urine protein concentration and urine analysis did not help to distinguish patients who developed permanent renal symptoms from patients with long-term normal kidney function. Life-long follow-up appears necessary in patients with AIN, especially if at least one negative prognostic marker was initially present.

Conclusion

Acute TIN is an important cause of acute renal failure in childhood. The causes that might lead to TIN are numerous, but a medication-induced hypersensitivity reaction is by far the most frequent. Kidney biopsy is the only method of confirming the diagnosis. In the case of renal failure intravenous steroids should be used rapidly in order to reduce the risk of renal fibrosis. In rare cases the progression towards end-stage renal disease occurs. Long-term follow-up is necessary in patients as clear predictions in patients at high versus low risk have not yet been established. Future effort is required to establish adequate strategies in steroid-resistant forms and to proceed towards individual tailoring of initial treatment strategies.