Acute interstitial nephritis: aetiology and management

Abstract

Acute interstitial nephritis (AIN) complicates a heterogeneous spectrum of diseases (see Table 1). Its characteristic histological lesion is the infiltration of the interstitial renal tissue by inflammatory cells (see Figure 1). AIN per se is a cause of acute kidney injury (AKI) and increasingly so: from 10 to 35% of the biopsy samples taken in AKI patients show AIN [1]. Renal impairment is occasionally severe and can be isolated, i.e. without gross proteinuria or haematuria. However, aseptic leucocyturia is found in one of the two cases [2]. While we are still short of non-invasive specific markers, urinary tumour necrosis factor α (TNF-α) and interleukin-9 were recently shown to perform well [3]. Renal biopsy ensures diagnosis of AIN, points to possible cause and informs prognosis. Historically reported during infectious disease such as scarlet fever or diphtheria, AIN is nowadays mainly due to drugs, including anti-infectious ones. In the 1960s, the first cases of methicillin- and phenindione-related AIN showed symptoms suggestive of hypersensitivity (rash, fever and eosinophilia) [4, 5], but today these symptoms are generally absent. Instead, symptoms such as asthenia, nausea or lumbar pain (due to renal oedema) are frequent but not specific. Drug-induced AIN remains one of exclusion, but an exhaustive list of patient medications (including self-medications) must be established in a patient with AIN. Antibiotics, non-steroidal anti-inflammatory drugs and proton pump inhibitors are the main culprits [1]. Theoretically, however, any drug can lead to AIN through an immune-allergic reaction. It has been suggested that humoral immunity is involved in this reaction because of the (exceptional) detection of antibodies directed against tubular basement membrane antigens [6], but experimental data strongly support the implication of cellular immunity [7]. The recent description of cases caused by immune checkpoint inhibitors [8] or TNF-α inhibitors [9] suggests a loss of tolerance against a native antigen expressed by renal cells (tubular or other). This hypothesis shares pathophysiological mechanisms with the alloimmune response observed in renal grafts during cell-mediated rejection, where lymphocytes infiltrate the tubular epithelium, inducing ‘tubulitis’, a lesion that can also be observed in native kidneys with AIN. How an antibiotic, for instance, can generate such a reaction is debated, but among other hypotheses, drugs may act as haptens, and cross-reactivity between native and drug epitopes—molecular mimicry—has been suggested [10]. Alternatively, drugs can also display a direct toxicity or crystallize within the tubular lumen, where they will initiate an inflammatory reaction, occasionally granulomatous, as has been described for atazanavir, ciprofloxacin and others [11, 12]. Enteric, food-derived oxalate ions are poorly available for intestinal absorption because they complex with calcium ions. In the case of fat malabsorption (after intestinal resection or gastric bypass, or in patients with a deficiency in exocrine pancreatic functions, or in patients exposed to orlistat, e.g. Ferraz et al. [13]), calcium is saponified with fat, which leaves oxalate ions unbound and free for absorption in the colon. Hyperoxalaemia ensues and hence hyperoxaluria. Such patients, if fed with oxalate-rich vegetables or fruits, may present with AKI. This is because of tubular obstruction, but also because precipitation of intratubular oxalate crystals, visible under a microscope using a polarized light, is frequently associated with renal inflammation [14]. Calcium oxalate crystals may indeed translocate into the renal interstitium and be picked up by endothelial cells or macrophages, where they will produce a danger signal and elicit inflammation through a mechanism involving the NLRP3 inflammasome [15–17]. Of note, intoxication with ethylene glycol (an oxalate precursor used as antifreeze) or ascorbic acid (another precursor) shows similar pathogenesis and association with metabolic acidosis [18]. Patients with active inflammatory bowel disease may similarly develop hyperoxaluria, but the differential diagnosis is occasionally complicated by the intake of 5-aminosalicylic acid, which is another cause of drug-induced AIN (typically observed within 3 years following the beginning of treatment) [19]. In this category of patients, renal biopsy is mandatory to distinguish isolated AIN from oxalate crystal nephropathy. Ingestion of orellanine-containing cortinar mushrooms can lead to AIN, sometimes granulomatous. Gastrointestinal symptoms will appear first (Day 3 post-intoxication), followed by renal damage (Day 8) [20]. There is no antidote and patients often progress to chronic renal failure. Sjögren’s syndrome, inflammatory bowel diseases, primary biliary cholangitis and sarcoidosis are known to cause AIN [1]. During lupus and antineutrophil cytoplasmic antibody-associated vasculitis, interstitial inflammation is one poss