1 Background

Acute interstitial nephritis (AIN) is a type of acute kidney injury (AKI) that involves an inflammatory infiltrate into the renal tubules and interstitium. It accounts for 15–20% of all AKI cases and is seen in up to 35% of biopsies for acute kidney injury of unknown causes [1]. The etiology of AIN is broad with the most common causes being medications such as antibiotics, NSAIDs, and proton pump inhibitors (PPIs) [2]. Other causes of AIN include autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjogren syndrome, as well as infections including cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Symptoms of AIN are often delayed from the onset of the offending agent. Patients may experience polyuria, rash, fevers, or arthralgias [1]. The definitive diagnosis of AIN relies on kidney biopsy and treatment includes removal of the offending agent, glucocorticoid therapy, and immunosuppression [1, 2].

Rosehips are a fruit that grows on wild rose plants (Rosa canina) [3]. These fruits are often used to make herbal teas and have been purported to have anti-inflammatory effects [4]. Rosehip tea has also been shown to reduce pain related to osteoarthritis [5,6,7]. In vitro analysis has suggested the anti-inflammatory effects of rosehip tea are via linoleic and alpha-linolenic acids which act to inhibit COX-1 and -2 [8, 9]. In this study, we report a unique case of AIN caused by excessive intake of rosehip tea.

2 Case presentation

A 67-year-old female with history of coronary artery disease, anxiety and attention deficit hyperactivity disorder presented to the emergency department for two months of worsening fatigue, polydipsia and polyuria. Three days prior to presentation she started to develop headaches, dizziness, nausea, and had one episode of emesis. Two months prior she started drinking approximately two liters of rosehip tea daily in an attempt to quench her sensation of dehydration. The patient denied any recent use of antibiotics, NSAIDs, PPIs, or lithium, however she was taking rosuvastatin and citalopram. She has no known family history of kidney disease.

Her work-up on admission was significant for a serum creatinine of 9.44 mg/dL (previously 0.8 3 years prior), BUN 95 mg/dL, phosphorus 6.6 mg/dL, carbon dioxide 12 mmol/L, and hemoglobin A1c 5.9%. Her urinalysis was positive for WBCs (> 10), RBCs (Many), bacteria (present), and Protein/Cr = 0.7. Urine culture was negative for infection and renal ultrasound revealed increased echogenicity without hydronephrosis or obstructing stones. The patient was initially suspected to have non-oliguric AKI vs. Acute tubular necrosis. She was started on intravenous normal saline and monitored for improvement in renal function and resolution of uremic symptoms. On hospital day 3 the patient’s renal function minimally improved (Cr. 8.40), she had persistent uremic symptoms, and she was started on hemodialysis (HD). On hospital day 4 a renal biopsy was performed (Fig. 1) which revealed AIN, a thin glomerular basement membrane, and five (23%) nodular sclerosed glomeruli. There was also moderate (30%) tubular atrophy and interstitial fibrosis. She started on prednisone and continued HD for 23 days. Two months after her initial presentation, the patient continued to have symptoms of AIN including polyuria leading to dehydration as seen on point of care ultrasound. She underwent repeat renal biopsy which showed persistent AIN. She tapered off prednisone and started on MMF with continued improvement in her renal function and AIN (Fig. 2).

Fig. 1
figure 1

Renal biopsy revealed inflammatory cells in the interstitium suggestive of AIN. A H&E stain 200×, B H&E stain, 400× Yellow arrows highlighting eosinophils

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Fig. 2
figure 2

Trend in serum creatinine since admission till day 187. Patient finished HD on day 26 and started on MMF on day 76

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The patient underwent extensive work-up to identify the etiology of her AIN to improve recovery and prevent relapse. As per her admission history and physical, she did not have any recent use of antibiotics, NSAIDs, PPIs, or Lithium. She was taking rosuvastatin and citalopram which were continued during her hospital admission and upon discharge. Her serology was negative for systemic disorders and infections including SLE, Sjogren syndrome, IgG4, HIV, and syphilis. Immunohistochemical staining from the initial renal biopsy was negative for CMV, HSV I, HSV II, and adenovirus. Given the negative work-up for causes of AIN, the etiology of the patient’s AIN is thought possibly to be due to excessive rosehip tea consumption.

3 Discussion and conclusions

AIN is commonly due to the exposure of offending agents, systemic disorders, or infections. Identifying the etiology for each patient is essential for disease management and treatment [1]. In the case presented, the etiology of her AIN was not initially clear. Although she did not have exposure to typical AIN inducing medications such as antibiotics, NSAIDs, PPIs, or Lithium, she was taking rosuvastatin and citalopram which have been reported to cause AIN [10, 11]. Given the rarity of cases and the risks of discontinuing both medications, the patient was recommended to continue taking both statin and SSRI. Due to hospital formulary, she was transitioned from rosuvastatin to atorvastatin while in-patient. Despite her continued statin and SSRI use, the patient’s AIN resolved. Thus, both were determined to be an unlikely cause of her AIN and we sought to identify an alternate etiology.

Herbal supplements have been used for their medicinal properties for thousands of years. It is only within the last century that medicine, particularly in the United States, has shifted towards a greater use of non-herbal pharmaceuticals [12]. This shift has led to a limited understanding of the purported benefits and potential risks of herbal supplements. Despite limited medical literature, nephrotoxicity of herbal supplements have been validated. In the early 1990’s Vanherweghem et al. reported nine cases of women consuming an herbal supplement for its intended weight loss benefits who ultimately developed rapidly progressive interstitial fibrosis [13]. The nephrotoxic compound was identified as aristolochic acid which is now also known for its carcinogenic properties [14,15,16,17]. Additionally, a cross-sectional study based in Taiwan showed that herbal therapy was independently linked to CKD in patients not using analgesics [18]. The causation of herbal induced nephrotoxicity is not well understood and is likely different among supplements. However, the renal clearance of herbal supplements and their metabolites is likely a contributing factor to pathogenesis [14].

While the mechanism in which rosehip tea causes AIN is unknown, we suggest a potential mechanism through the metabolism of the polyunsaturated fat arachidonic acid (AA). Rosehips produce AA with the highest concentrations occurring early in development [19]. In vivo AA is metabolized through three separate pathways, COX, LOX, and CYP450. Metabolites from each of these pathways have been associated with kidney inflammation [20]. In the COX pathway AA is metabolized into prostaglandins which have been shown in multiple disease states to promote inflammation [20]. In the LOX pathway AA is metabolized into leukotrienes and lipoxins [20]. Leukotrienes are chemotactic molecules that promote leukocyte migration leading to an inflammatory cascade. Lastly, in the CYP450 pathway AA is metabolized to hydroxyeicosatetraenoic which activates peroxisome proliferator-activated receptor Y in renal macrophages leading to inflammation in the tubule-interstitial cells [20]. Despite the pro-inflammatory metabolites of AA, rosehip tea is reported to have anti-inflammatory benefits; likely via inhibition of the COX pathway. When rosehip tea is consumed in small quantities, the anti-inflammatory benefits of COX inhibition likely outweigh the relatively small pro-inflammatory metabolites of AA. Additionally, at these small quantities of rosehip consumption, the level of AA may not be sufficient to incur AIN. However, when rosehip tea is consumed in excessive quantities, it is possible that the pro-inflammatory metabolites of LOX and CYP450 begin to have a clinical effect that may lead to AIN. Therefore, we propose that intake of rosehip tea, especially if harvested in the early stages of development, could lead to an accumulation of arachidonic acid and its metabolites perpetuating inflammation and leading to AIN.

While the aforementioned mechanism of AIN is possible, there are alternative mechanisms that may contribute to AIN from rosehip tea. First, a toxin or compound either produced by rosehips or added to the tea could precipitate AIN. Further analysis of rosehip tea would be necessary to isolate compounds within rosehip tea and evaluate their role in AIN. Alternatively, the patient in this case was continued on her statin and SSRI throughout hospitalization and upon discharge. As statins are metabolized via the CYP450 pathway, it is possible that the metabolism of her statin altered the metabolism of rosehip tea. This may lead to increased metabolites of AA that cause AIN. Further studies should be done to evaluate how statins change the metabolism of rosehip tea.

The concentration of arachidonic acid needed to cause AIN would likely need to be from excessive intake of rosehip tea. Patient consumption of rosehip tea at levels necessary to cause AIN may likely be due to the inherent nature of the laxative and diuretic properties [4, 21]. For instance, the patient in this case was consuming up to 2L of rosehip tea daily for approximately 2 months. Given the volume depleting effects of rosehip tea, we theorize this patient experienced a positive feedback cycle of rosehip tea intake. Despite consuming two liters a day, she still experienced the sensation of dehydration leading to a self-perpetuating cycle of excessive intake. The level of rosehip tea consumption in this patient likely led to concentrations of arachidonic acid capable of causing AIN.

After removal of the offending agent, treatment of AIN typically includes the use of immunosuppressive agents. Steroids are often used as first-line therapy and have a signal towards better outcomes when initiated early [1, 22, 23]. In the case presented, the patient had modest improvement in renal function with steroids, and ultimately required MMF for full resolution of her AIN. The time to recovery in this case was likely due to the prolonged exposure of the offending agent leading to advanced disease at presentation (Fig. 1). In cases of AIN without systemic symptoms, as in this case, patients often present and/or are diagnosed late in the disease course. These late presenters often require renal replacement therapy and have delayed resolution of their symptoms [1].

Further studies are necessary to establish the health benefits, and importantly the potential side effects of herbal teas including rosehip tea. In this unique case, rosehip tea was suspected to be the etiology of AIN. The removal of rosehip tea from the patient’s diet in conjunction with immunosuppressive agents improved the patient's renal function and symptoms of AIN. Providers should be aware when counseling patients that excessive amounts of rosehip tea may lead to AIN.