Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. TIN accounts for approximately 2%–3% of native renal biopsies.1–3 In biopsies to evaluate acute renal failure of unknown origin, TIN represents about 13% of cases in adult patients.2 3 Reliable data on the incidence and prevalence of paediatric TIN are lacking.

Renal histopathology in TIN is characterised by interstitial cellular infiltrates and oedema, but vessels and glomeruli are typically spared.4 The inflammatory process may eventually lead to interstitial fibrosis and chronic kidney disease.5

Numerous causes of TIN are known, with drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), being the trigger in 60%–70% of cases6; however, the identity of the causative agent in cases of TIN is usually speculative. Other cases of TIN are related to infections or systemic diseases. In some cases, renal disease can be accompanied by uveal inflammation (tubulointerstitial nephritis with uveitis (TINU)).7 8 Other TIN cases are presumed to be idiopathic.4 Despite the different aetiologies of TIN, a common immune-mediated pathogenic mechanism is assumed. Antigen-mediated cellular immune responses seem to play a key role in the pathogenesis of TIN.3 9 It is also important to note that this is a very heterogeneous group of patients. While histopathology is similar, TIN due to sarcoidosis is probably biologically distinct entity from that due to antibiotics, recreational drugs, NSAIDS and infectious agents. Clinical symptoms of TIN are often non-specific and therefore may lead to delayed diagnosis and treatment.4 10

Corticosteroids are well established in the treatment of severe TIN, although prospective randomised controlled clinical trials assessing the indications and efficacy of corticosteroid treatment are not available. In adult patients, retrospective data indicated beneficial effects of corticosteroids on renal function recovery in drug-induced TIN.11–14 However, results of other retrospective studies did not support the routine administration of corticosteroid therapy.1 15 Results from a small prospective paediatric study showed an accelerated renal recovery with corticosteroid treatment.16 There is very limited experience of the use of other immunosuppressive agents (eg, mycophenolate mofetil (MMF)) in patients with TIN. Moreover, there is no consensus on a standard therapeutic regimen (eg, intravenous vs oral administration, dosage and duration of therapy) in either children or adults.

In this study, we assessed the aetiology, therapy and clinical course of TIN in a large paediatric cohort with manifestation of acute TIN between 2007 and 2018. Data were collected retrospectively via a survey circulated to members of the German Society of Pediatric Nephrology (GPN), European Society of Pediatric Nephrology (ESPN), European Network of Rare Kidney Diseases (ERKnet) and Pediatric Nephrology Research Consortium (PNRC) based in the USA.

Members of GPN, ESPN, ERKNet and PNRC were invited to participate in the online survey. An email invitation with a summary of the project and a link to an online questionnaire service provider (https://www.google.de/intl/de/forms/about/) was sent to all mailing list contacts of GPN, ESPN, ERKNet and PNRC. The survey was launched in April 2018 and was closed in June 2019.

The data collection was retrospective and fully anonymised. Only patients with biopsy-proven TIN were included in the study. Further inclusion criteria were age between 0 and 18 years, and presentation of disease was between 2007 and 2018.

The questionnaire comprised 57 items. Answers were given as multiple choice or short free texts assessing the incidence, aetiology and course of acute TIN in children. ‘Yes’, ‘no’ and ‘not assessed’ were given as answer options for disease symptoms, urinary findings and biopsy results. Free-text answers were required for precise causative factors for TIN (eg, drug name, pathogen, underlying systemic disease). The questionnaire is provided in the online supplemental material.

Creatinine-based ‘Bedside Schwartz’ formula (estimated glomerular filtration rate (eGFR)=0.413 × (height/Scr)) was used for eGFR.17

The responses were automatically collected in a database provided by the survey administration app. All statistical data analyses were performed in GraphPad Prism V.8 (https://www.graphpad.com). Continuous variables were expressed as median, and range as no normal distribution was assumed. Three different non-parametric tests were used for analysis of non-normally distributed variables: Mann-Whitney U test and Kruskal-Wallis test were used, respectively, to compare medians of two groups and three or more groups of variables not normally distributed; one sample Wilcoxon test was conducted for comparison of paired data. Statistical significance of dichotomous variables was measured by using the χ² test. P<0.05 was considered statistically significant.

The study was approved by the council of the ESPN, GPN, ERKNet and PNRC. Requests for authorisation by the ethics committees of the other centres were not considered necessary because this was a survey that simply collected the experience and practices of the physicians, and it did not involve approaching patients directly or seeking any patient-specific data.

Thirty-nine clinicians from 18 countries participated in the survey. One hundred and seventy-one patient cases were included in the final analysis. Patients originated from Northern Europe (n=41), Southern Europe (n=38), Western Europe (n=25), Eastern Europe (n=8), Western Asia (n=31), Southern Asia (n=1), Southeastern Asia (n=5) and Northern America (n=22).

Gender distribution was equal with 93 (54%) females and 78 males (46%). The median age (range) was 13 (1–17) years at diagnosis with the following age distribution: 1–5 years: 9% (16/171); 6–12 years: 38% (64/171); 13–18 years: 53% (91/171) (see figure 1).

The results of this survey shed some light on cause, clinical management and outcome of TIN in paediatric patients. To the best of our knowledge, our findings are from the largest paediatric TIN cohort to date.

The clinical presentation of TIN was unspecific with fatigue, vomiting or nausea and fever being the most frequent features. Only one patient of 171 (0.6%) showed the ‘classic’ triad of fever, arthralgia and skin rash or exanthema that dominated the clinical picture in early reports of mainly drug-induced cases. Actually, this symptom triad occurred in 5%–10% of patients in earlier reports.9 18

Drug-induced TIN is the underlying cause in 60%–70% of cases in adults.6 18 In our cohort, drugs were responsible for only 30% of TIN cases. The fact that only biopsy-proven cases were included in our analysis might be responsible for a lower percentage of drug-induced cases since in clinical practice patients with typical clinical hallmarks of drug-induced TIN and mild to moderate renal failure do not always undergo renal biopsy. NSAIDs and antimicrobials are the most common culprits in drug-induced TIN.6 19 Whether NSAIDs or antimicrobials are the leading class of drugs in the aetiology of TIN, however, is a matter of debate.1 11 20 21 In our paediatric cohort, NSAIDs were identified as the leading cause in 48% of patients with drug-induced TIN, and another 10% had a history of NSAIDs plus antimicrobial intake. Coadministration of two or more drugs can make it difficult to identify the culpable agent, but NSAIDs clearly represent the main cause for drug-induced TIN in our study, followed by antibiotics (21% of drug-induced cases). Although proton-pump inhibitors (PPIs) are a widely prescribed class of drugs and have been considered a relevant cause of acute TIN since the first published report of PPI-induced TIN in 1992,22–25 no case of PPI-induced TIN was found in our cohort.

Remarkably, three patients had a history of herbal medicine intake. Aristolochic acid and other plant alkaloids have been identified as nephrotoxic ingredients in Chinese herbal medicine, and interstitial nephritis is one possible manifestation of its nephrotoxic capacity.26 27 Furthermore, interstitial nephritis was triggered by bee stings in two patients. Acute kidney injury due to immune-mediated acute interstitial nephritis has been reported as a rare complication of Hymenoptera stings (bees and wasps) in a number of case reports or case series.28–30 Another patient developed acute TIN after smoking a potentially nephrotoxic substance. A number of legal and illegal drugs should be taken into consideration as possible triggers of TIN, particularly in adolescents. For example, synthetic cannabinoids have become popular recreational drugs with Δ9-tetrahydrocannabinol-like effects that are solubilised, sprayed onto herbal mixtures and usually smoked. Renal manifestations of synthetic cannabinoid use are acute tubular necrosis and acute interstitial nephritis.31 Our results show that a variety of drugs, medications and toxic agents are involved in the pathogenesis of acute interstitial nephritis and should be considered as a potential aspect of the patient’s medical history.

TIN was associated with systemic diseases in 7% of patients. In adults, systemic diseases underlie 10%–15% of cases.19 Sjögren’s syndrome and sarcoidosis are well described autoimmune disorders with TIN as typical renal manifestation. Interstitial nephritis is the prevalent renal finding in Sjögren’s syndrome; 98% of patients with renal involvement show TIN in renal biopsy.32 TIN associated with APECED type 1,33 34 microscopic polyangiitis,35 familial Mediterranean fever,36 37 rheumatoid arthritis38 and malignant infiltration39 has been described in the literature. The case of a 17-year-old girl with atypical haemolytic uraemic syndrome and acute TIN included in our analysis has also been described by Basak et al.40

Infectious causes were found in 4% (in adults 5%–10%19). Only viral and no bacterial, fungal or parasitic pathogens were identified. Adenovirus, BK polyoma virus (both predominantly in renal transplant patients) and hepatitis C have been described as infectious causes of TIN.41–43 Three patients had symptoms of upper respiratory tract infection without pathogen identification, and rhinovirus was identified in another patient. It remains unclear if a bacterial or viral pathogen was the unequivocal cause of TIN in these cases or if other underlying factors played a role in the pathogenesis (eg, intake of NSAIDs or antibiotics to treat respiratory symptoms). It has to be noted that all diagnoses were established by the participating physicians based on biopsy results and clinical findings.

TINU is thought to be a rare condition with an incidence of uveitis among TIN patients of less than 10%.18 Jahnukainen et al44 reported that uveitis was diagnosed in 46% in a case series of 26 children with ‘idiopathic TIN’, supporting the assumption that the prevalence of uveitis among TIN patients is higher than previously assumed. In our study, 58% of TINU patients had no ocular symptoms at onset of renal disease. This is in line with previous reports that uveitis may evolve up to 14 months after the onset of TIN45 46 and that a high percentage of TINU patients are ophthalmologically asymptomatic at the onset of renal symptoms.44 Thorough ophthalmological examinations over months after the onset of TIN are necessary even in patients without ocular symptoms.44 46 Our results support the rationale for this recommendation.

In our study, the overall renal outcome 3–6 months after diagnosis of TIN was favourable with a rise in median eGFR from 31 to 86 mL/min/1.73 m². Only 2% (two patients with idiopathic TIN, one patient with drug-induced TIN and another patient with systemic disease) had eGFR <15 mL/min/1.73 m² (CKD 5).

The role of corticosteroids in the treatment of TIN has remained controversial. Available studies in adults are retrospective and not controlled and deliver partially contradictory results.1 11–15 A prospective paediatric study with 17 patients showed that prednisone speeds up renal recovery, but there was no significant difference in renal function between prednisone and control patients after 6 months’ follow-up.16

In our study, renal function improved significantly after 2 weeks and showed further significant improvement 3–6 months after kidney biopsy. This development of eGFR was found in all aetiological subgroups. Corticosteroid treatment of TIN seems well established among paediatric nephrologists, since 80% of included patients received steroids. Whereas patients who were not treated with steroids had a significantly better median eGFR than patients who underwent steroid therapy at time of renal biopsy, there was no significant difference in eGFR 2 weeks and 3–6 months later and the rate of glomerular and/or tubular proteinuria 3–6 months later. However, we were not able to evaluate the efficacy of corticosteroid treatment of acute TIN since the number of patients was not equally distributed between the steroid-treated and untreated group (80% receiving steroid treatment) and long-term effects of corticosteroid treatment were not monitored. MMF is an additional treatment option in paediatric TIN patients with different etiological backgrounds but was exclusively used in combination with corticosteroids (the exception being one patient with APECED type 1 syndrome, treated with MMF and rituximab). MMF has been described as a successful therapeutic option for steroid-resistant or intolerant patients.47