Acute kidney injury and nephrotic syndrome associated with eltrombopag therapy in chronic idiopathic thrombocytopenic purpura
- 1 Respiratory, Princess Alexandra Hospital NHS Trust, Harlow, UK
- 2 James Paget University Hospitals NHS Foundation Trust, Great Yarmouth, Norfolk, UK
- Correspondence to Dr Suchi Anindita Ghosh; suchi.ghosh@nhs.net
Abstract
A 77-year-old man was admitted with severe acute kidney injury and nephrotic syndrome. He was started on eltrombopag for chronic idiopathic thrombocytopenic purpura 6 weeks earlier. An ultrasound of the kidneys was normal and an auto-antibody screen was negative. The use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient’s development of acute renal failure and eltrombopag therapy. Literature review identified only one other case of nephrotic syndrome and acute kidney injury associated with eltrombopag therapy in which a kidney biopsy revealed focal segmental glomerulosclerosis. Due to the challenges faced during the prevailing SARS-CoV-2 pandemic and persistent low platelet counts a renal biopsy was not undertaken. On stopping eltrombopag, the patients renal function stabilised and he successfully went into remission following treatment with high dose corticosteroids and diuretics. This report of a serious case of reversible renal failure and nephrotic syndrome after treatment with eltrombopag may serve to inform clinicians about the possible severe renal adverse effects of eltrombopag before its commencement for future use.
Background
Eltrombopag, an orally available non-peptide thrombopoietin receptor agonist, is used for the treatment of thrombocytopenia of various causes, including chronic idiopathic thrombocytopenic purpura (ITP) and hepatitis C-related liver cirrhosis.1 2
So far, there has been only one reported case of nephrotic syndrome and renal failure associated with eltrombopag therapy.3
We describe a 77-year-old man who developed acute kidney injury and nephrotic syndrome after treatment with eltrombopag. Although the exact mechanism of eltrombopag related renal failure is unclear he was successfully treated with the cessation of the drug and commencement of high-dose steroids. To the best of our knowledge this is only the second reported case of acute kidney injury and nephrotic syndrome associated with eltrombopag therapy in ITP. Through this case we aim to inform clinicians about this probable serious adverse effect of eltrombopag and the need for closer monitoring of renal function in patients commenced on eltrombopag.
Case presentation
A 77-year-old man with a background of hypertension was diagnosed with ITP in February 2014. He had poor responses to high-dose steroids and mycophenolate mofetil, and variable response to romiplostim, a fusion protein analogue of thrombopoietin. In January 2020, eltrombopag was started at 50 mg daily dosage. At the start of eltrombopag, blood tests showed an estimated glomerular filtration rate (eGFR) of 78 mL/min/1.73m2 and platelet count of 7×109 g/L. Six weeks after the commencement eltrombopag, the patient was admitted with a 4-week history of progressive leg swelling and breathlessness. On examination he had gross pitting peripheral oedema and bilateral pleural effusions. His renal biochemistry showed a drop in eGFR to 25 mL/min/1.73m2 (figure 1) and 3+ protein in urine dip stick. Albumin level was 20 (range 35–50 g/L) and platelet count of 29×109 g/L. His urine protein–creatinine ratio was 1151 mg/mmol (normal <35 mg/mmol). A diagnosis of acute kidney injury with nephrotic syndrome was made. An acute and auto-antibody screen (table 1) including antinuclear antibodies, antineutrophilic cytoplasmic antibodies, antiglomerular basement membrane antibodies and antiphospholipase 2 receptor antibodies were negative. PCR test for COVID-19 was also negative. A drug history did not reveal any other potential nephrotoxins. A renal ultrasound showed normal size and shape of both kidneys with no evidence of obstruction. A renal biopsy was not undertaken due an increased risk of bleeding as the patient’s platelet counts were consistently under 30×109 g/L (range 150–400×109 g/L). His clinical presentation was at the onset of the global SARS-CoV-2 pandemic which also resulted in significant operational challenges to conduct a renal biopsy.
Serological investigations done on admission
| Serological test | Result | Reference range |
| Antineutrophilic cytoplasmic antibodies | Negative | |
| Antinuclear antibodies | Negative—0.2 | (0.0–1.0) |
| Antiglomerular basement membrane antibodies | Negative—<1.9 Elia U/mL | (0.0–10.0 Elia U/mL) |
| Antiphospholipase 2 receptor antibody | Negative | |
| Serum electrophoresis | Negative for paraproteins | |
| IgG | 5.6 g/L | (6.0–16.0 g/L) |
| IgA | 2.59 g/L | (0.8–4.0 g/L) |
| IgM | 0.94 g/L | (0.5–2.0 g/L) |
| Complement C3 | 1.12 g/L | (0.75–1.65 g/L) |
| Complement C4 | 0.21 g/L | (0.14–0.54 g/L) |
| Rheumatoid factor | <20 IU/mL | <30 IU/mL |
| Hepatitis B surface antigen | Not detected | |
| Hepatitis C antibodies | Not detected | |
| HIV 1 and 2 | Not detected | |
| SARS-CoV-2 PCR | Not detected |
Renal function (eGFR) over time, with eltrombopag therapy and clinical management as shown.
Treatment
Given the temporal relationship between the commencement of eltrombopag and the onset of proteinuria with renal failure, it was decided to discontinue eltrombopag. Using the Naranjo adverse drug reaction probability scale,4 our patient scored a 5, indicating a probable relationship between eltrombopag and the patients clinical presentation. Following literature review a similar case was identified where the renal lesion was diagnosed as focal segmental glomerulosclerosis (FSGS) on renal biopsy.3 Drug induced acute tubulo-interstitial nephritis was also a possible differential diagnosis. Therefore, a decision was made to administer empirical treatment with high dose prednisolone starting at 60 mg/day. There was excellent response to this and his eGFR improved to 72 mL/min/1.73m2 and urine PCR dropped to 107 mg/mmol (figure 2).
Time course of urine PCR from the diagnosis of nephrotic syndrome to recovery that is, week 4 suggests 4 weeks since starting eltrombopag therapy. Eltrombopag was stopped at week 6 but urine PCR was not recorded at this time.
Outcome and follow-up
There was excellent response to treatment and his eGFR improved to 72 mL/min/1.73m2 and urine PCR dropped to 107 mg/mmol (figure 2). As shown, by week 24, our patient’s renal function was back to baseline and he was successfully weaned off corticosteroids and furosemide. He was started on an alternative therapy for his chronic ITP.
Discussion
Eltrombopag is a thrombopoietic receptor agonist which is used for the treatment of ITP and thrombocytopenia associated with hepatitis C related cirrhosis. Renal failure and nephrotic syndrome are rarely reported as its adverse effects. Renal tubular toxicity has been observed in animal studies5 but no episodes of renal dysfunction has been reported in published trials. Both phase I and phase II studies of eltrombopag have reported non-specific symptoms such as influenza-like illness, arthralgia, myalgia, constipation, diarrhoea and pruritus.5 6 However, at doses of 30–75 mg used in clinical trials, eltrombopag therapy was discontinued in three patients because of abdominal pain and ascites (30 mg), neutropenia (50 mg) and retinal exudates (75 mg).2 So far, there have been two case reports of eltrombopag associated acute renal failure.3 7 In the first case a 54-year-old man with antiphospholipid syndrome and ITP developed acute renal failure with eltrombopag. There was no associated nephrotic syndrome. On cessation of the drug, renal function improved to baseline therefore, a renal biopsy was not carried out.7 In the second case, the patient developed acute renal failure and nephrotic syndrome after seven doses of eltrombopag which was given for ITP. Her renal biopsy confirmed FSGS.3
Potential mechanisms of eltrombopag-related kidney injury remain speculative. Eltrombopag appears to be highly specific for the thrombopoietin receptor and as this receptor is not believed to be expressed in the kidney, it is unlikely that potential eltrombopag nephrotoxicity is a manifestation of intrarenal signalling. Eltrombopag enhances proliferation and differentiation of megakaryocytes in human bone marrow by binding to the transmembrane domain of the thrombopoietin receptor with high specificity. The megakaryocyte pathway triggers the activation of the cytoplasmic tyrosine kinases Janus kinase 2 and tyrosine kinase 2, which in turn activate signal transducers and activators of transcription 5, phosphoinositide‐3 kinase and Ras‐mitogen‐activated protein kinase (MAPK).8 In animal models, the activated megakaryocytes release transforming growth factor-beta,9 which also activates MAPK-ERK and PI3K pathways in podocytes and leads to podocyte apoptosis and the development of glomerulosclerosis.10 This results in massive proteinuria.
Although we do not have a tissue diagnosis due to severe thrombocytopenia and the challenges faced due to the prevailing pandemic, the temporal relationship between the commencement of elltrombopag and development of acute renal failure and nephrotic syndrome is quite strong. The absence of other causes and case reports of a similar presentations support our inference. The medication summary of product characteristics also mentions nephrotic syndrome as an uncommon adverse effect.11 In summary our patient experienced acute renal failure and severe proteinuria after treatment with eltrombopag. Although the mechanism for eltrombopag-related renal failure is unclear, discontinuation of the drug and empirical treatment with corticosteroids rescued this patient from end-stage renal disease. This is an important case report to highlight this clinical association and we hope this will alert clinicians in the future to monitor renal function and proteinuria closely for patients starting this medication.
Learning points
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This is the only second reported case of nephrotic syndrome and severe acute kidney injury associated with eltrombopag therapy.
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Prompt cessation of the drug and treatment with empirical steroids avoided the need of renal replacement therapy in this patient.
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Closer monitoring of renal function and urine for proteinuria is recommended in patients who are commenced on eltrombopag.
Footnotes
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Contributors Supervised by JP. Patient was under the care of KZM and JP. Report was written by SAG and JP.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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