NADIA Chaudhury,1 ALEXANDROS L Liarakos,1 KISHORE Gopalakrishnan,2 WAQAR Ayub,3 NARASIMHA Murthy,1 RANGANATHA Rao1
1 WISDEM Centre, Department of Endocrinology and Diabetes, University Hospitals Coventry and Warwickshire NHS Trust
2 Department of Histopathology, University Hospitals Coventry and Warwickshire NHS Trust
3 Department of Renal Medicine, University Hospitals Coventry and Warwickshire NHS Trust
Address for correspondence: Dr Nadia Chaudhury
University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX, UK
E-mail: nadia-chaudhury@hotmail.co.uk
https://doi.org/10.15277/bjd.2021.321
Br J Diabetes 2021;21:228 - 232
Key words: GLP-1 receptor agonists, liraglutide, renal impairment, acute kidney injury, nephrology, renal, diabetes
Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is a recognised treatment for type 2 diabetes mellitus (T2DM). It mimics human GLP-1 and works by augmenting insulin secretion, inhibiting glucagon secretion and inhibiting gastric acid secretion.1 It has been shown to not only improve glycaemic control in people with diabetes, but also result in weight loss, reduced hypoglycaemic episodes, reduced albuminuria, reduced progression to macroalbuminuria and reduced incidence of myocardial infarction and stroke events.2–5 Gastrointestinal upset is the commonest reported side effect, which occurs in up to 56% of patients in clinical trials. Furthermore, BNF recommends avoiding liraglutide treatment in end-stage renal disease/estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 (depending on brand), due to the increased risk of adverse events.
We present a rare case of a female with chronic kidney disease (CKD), whose treatment with liraglutide was associated with rapid deterioration of renal function and tubulointerstitial nephritis. Our literature search highlighted one previous case, thus we would like to raise awareness of this potential rare side effect of liraglutide treatment.6 We have further conducted a literature search of all case reports noting associations of glucose-lowering therapies with acute interstitial nephritis to raise awareness of this potential complication.
A 59-year-old woman with T2DM and CKD stage 3 (G3b A1), maintained stable glycaemic control with HbA1c 58 on linagliptin 5 mg once daily and reduced carbohydrate diet. Medication history also included amlodipine 5 mg and atorvastatin 20 mg. She was started on liraglutide in January 2019 to improve her metabolic control further. Linagliptin treatment was discontinued, given that the combination of linagliptin and liraglutide is unlikely to provide synergistic effects and is not cost effective. Despite improvement in glycaemia, rapid deterioration in renal function was noted subsequent to starting liraglutide (Table 1 and Figure 1).
There was no other explanation for the drop in eGFR: she did not experience diarrhoea, nausea or vomiting. Weight and BMI had remained stable throughout liraglutide treatment at 70 kg and 24.3 kg/m2, respectively. Furthermore, blood pressure remained stable at around 120/70 mm Hg. She had remained euvolaemic whilst on liraglutide treatment. She had not taken NSAIDs. Urinalysis was bland. Complement C3 and C4, double-stranded DNA 1 (dsDNA1), anti-neutrophil cytoplasm antibodies (ANCA), myeloperoxidase (MPO) and anti-proteinase 3 antibody (PR3) were all negative. Ultrasound of the kidney showed normal kidneys bilaterally (right 10.7 cm, left 10.4 cm) and no evidence of obstruction. Moreover, there was no family history of renal disease.
As the rapid drop in eGFR was only noted after commencing liraglutide, it was postulated that the loss in renal function may be due to liraglutide initiation. Unfortunately, due to a delay in the medical appointments, the only available eGFR results were prior to and at 5 months after start of treatment, thus complicating matters further. The eGFR was 35 mL/min/1.73 m2 prior to starting liraglutide and dropped rapidly to 17 mL/min/1.73 m2 when measured five months later – a significant fall of 51%. It was therefore decided to stop liraglutide treatment in May 2019 and her linagliptin was restarted.
Renal biopsy was performed in July 2019 (Figure 2). Significant interstitial fibrosis and tubular atrophy (IFTA) were present, with profound interstitial inflammatory infiltrate and mild focal tubulitis. All these findings heavily supported the diagnosis of acute interstitial nephritis. Furthermore, mild glomerular mesangial expansion and arteriolar hyalinosis was seen, suggestive but not specific for a diagnosis of diabetic nephropathy. We therefore concluded that the kidney biopsy showed significant acute interstitial nephritis with mild diabetic nephropathy.
Despite stopping liraglutide, her renal function did not improve (Figure 1). She progressed to end stage renal disease. Steroid treatment was considered but not deemed beneficial due to severe IFTA and her diabetes. She has started peritoneal dialysis and is awaiting renal transplant.
Acute interstitial nephritis is a common cause of acute kidney injury (AKI), and has been identified in the diagnosis of 12.9% of kidney biopsies from patients with AKI.7 The main cause of acute interstitial nephritis in the developed world is medications, which contribute to >70% of cases.8 Antibiotics, NSAIDs, anti-inflammatory agents, anticonvulsants, diuretics and proton pump inhibitors are the most common culprits.9,10 Other causes of interstitial nephritis include infections, autoimmune disorders, systemic diseases, metabolic causes and environmental exposure.11 The presentation of drug- induced acute interstitial nephritis is highly variable.12 The classic triad of symptoms of rash, fever and eosinophilia are only witnessed in <10% of patients.9 Laboratory tests and imaging are usually unhelpful in the diagnosis of drug-induced acute interstitial nephritis as they lack both sensitivity and specificity.9,12 Renal biopsy is the gold standard investigation to make a definitive diagnosis. Main histological findings include interstitial inflammation, comprising primarily of lymphocytes and monocytes, and tubulitis is evident. If the nephritis continues to deteriorate, chronic appearances of interstitial fibrosis and tubular atrophy may be present.9
Our case highlights a person with stable diabetes and established CKD whose kidney function rapidly deteriorated further after liraglutide initiation. People with diabetes and CKD3 are expected to experience a progressive decline in eGFR of 1.9–3.3 mL/min/1.73 m2 per year.13 In contrast, our case experienced a decline in eGFR of 18 mL/min/1.73 m2 within 5 months. Due to the time correlation between eGFR decline and initiation of liraglutide, it was highly suggestive that this decline was due to liraglutide therapy; we could not determine any other reason for such a rapid decline in eGFR.
There have been similar case reports to ours in the literature where use of liraglutide (and other antidiabetic medications) resulted in acute interstitial nephritis (Table 2). These cases, like ours, experienced no gastrointestinal symptoms thus no dehydration, yet deterioration in kidney function was evident. Renal biopsy supported the diagnosis.
It is speculated whether this injury results from an immunological response. Pathogenesis of drug-induced acute interstitial nephritis is thought to occur from type IV delayed hypersensitivity reaction to the offending medication. This can happen within days or months of exposure to the medication in question. It is unclear exactly how this process occurs, however suspected mechanisms include molecular mimicry or direct binding of hapten drug to tubular membrane, resulting in an immunogenic response.12 Furthermore, antibody production has been shown to occur after liraglutide introduction (~8.5% of cases).14
Current standard of care for treatment of drug-induced acute interstitial nephritis involves early recognition of the culprit drug and discontinuation of the medication. Late recognition of kidney damage and continued drug use may result in kidney fibrosis, with 40–60% of people with acute tubulointerstitial nephritis ultimately developing chronic kidney disease.8 Corticosteroid therapy is controversial in the treatment of drug-induced acute interstitial nephritis. Some studies report rapid and complete recovery of baseline renal function in those treated with steroids,15,16 whilst others have failed to confirm these findings.17,18 No prospective randomised controlled trials investigating corticosteroid treatment in acute interstitial nephritis have been conducted as yet. Multicentre prospective randomised controlled trials are needed to study the effect of corticosteroid therapy on interstitial nephritis. Nevertheless, the main conclusion from all studies investigating steroid treatment is that the earlier steroid treatment was initiated, the better the prognosis.19
The situation is further complicated when using steroids to treat acute interstitial nephritis in people with diabetes due to glucocorticoid-induced hyperglycaemia.20 Furthermore, it has been noted in the literature that people with diabetes are less likely to respond to steroid treatment. In addition, interstitial fibrosis in renal biopsy is associated with poor response to steroids.21 This may be due to fibrosis indicating irreversible damage of renal tissue. In our case, as significant interstitial fibrosis and tubular atrophy was noted on renal biopsy, it was deemed that steroid therapy would not be beneficial. Furthermore, with our patient’s diabetes under stable control, steroid therapy was avoided to ensure HbA1c did not deteriorate.
Of interest, liraglutide and other GLP-1 agonists have been reported to cause acute kidney injury via a different pathogenesis. Those affected severely by the gastrointestinal side effect of liraglutide treatment may experience dehydration and progress to acute kidney injury. In these patients, renal biopsy confirms acute tubular necrosis. Careful fluid balance and examination is necessary to determine intravascular volume depletion. Fluid rehydration is essential in the treatment of these patients.22,23 This represents a diagnostic challenge for physicians, whereby clinical and laboratory features are comparable for both acute tubulointerstitial nephritis due to medication and acute tubular injury due to dehydration.24 Especially in people with diabetes, the complexity for diagnosis of renal disease is challenging. However, as our case experienced no gastrointestinal side effects, had stable weight and blood pressure and was clinically euvolaemic throughout liraglutide treatment, it was unlikely she had kidney function deterioration via this mechanism. Histological investigation further confirmed our suspicions, and excluded volume depletion as a cause of her eGFR deterioration.
Despite our case report, we would like to highlight the multiple studies reporting the benefit of liraglutide on metabolic, cardiovascular and renal outcomes.2–4 Furthermore, post hoc analysis of people with CKD have further shown the safety and efficacy of liraglutide treatment, and its benefits in reducing all-cause mortality in this patient subtype.25,26 We therefore conclude that liraglutide has a positive impact on renal function. However, physicians should be aware of acute interstitial nephritis as a possible rare side effect.
Despite the multiple cardiovascular and renal benefits of liraglutide therapy, our case highlights a rare side effect – acute interstitial nephritis. Few cases have been reported in the literature, thus high clinical suspicion needs to be maintained in those with rapid renal deterioration after liraglutide (and other antidiabetic medication) initiation. If interstitial nephritis is suspected and volume depletion has been excluded as a differential diagnosis, the gold standard investigation is renal biopsy. Definitive management of antidiabetic medication-induced acute interstitial nephritis involves identification and removal of the offending medication. Steroid therapy is controversial, with a limited effect noted in those with diabetes. From our case we thus aim to raise awareness to clinicians about a rare possible side effect of liraglutide (and other antidiabetic medication) therapy and highlight its investigation and management.
Conflict of interest WA: Payment or honoraria for lectures: AstraZeneca. KG: None. NM: Payment or honoraria for lectures: Napp Pharmaceuticals, AstraZeneca, Eli Lilly; support for attending meetings: Novo, AstraZeneca. NC: Support for attending meeting: SFE BES registration grant to attend SFE BES Conference 2021. ALL: Support for attending meetings: AstraZeneca. RR: Honorarium from Eli Lilly for presentation on empagliflozin in Cardiology Department at UHCW; support for attending meetings: Napp.
Funding None.
References for Table 2
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