Nephrol Dial Transplant (2015) 30: 1225–1229 doi: 10.1093/ndt/gfv222
The Bench-to-Bedside Transition Bortezomib-induced acute interstitial nephritis Wisit Cheungpasitporn1, Nelson Leung1,2, S. Vincent Rajkumar2, Lynn D. Cornell3, Sanjeev Sethi3, Andrea Angioi1 and Fernando C. Fervenza1 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA, 2Division of Hematology, Mayo Clinic, Rochester, MN, USA
and 3Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
Correspondence and offprint requests to: Fernando C. Fervenza; E-mail: [email protected]
A B S T R AC T Acute interstitial nephritis (AIN) is one of the important causes of acute kidney injury (AKI) resulting from inflammatory tubulointerstitial injury induced by medications, infections and systemic diseases. Bortezomib has been increasingly used especially in renal related indications such as multiple myeloma and monoclonal gammopathy of renal significance. Severe allergic reactions from bortezomib treatment including AIN have not been described in the literature. We report a 47-year-old white man who developed biopsy-proven allergic AIN after treatment with bortezomib for his C3 glomerulonephritis. The patient’s kidney function improved after treatment with glucocorticoid therapy and discontinuation of bortezomib, but worsened with recurrent AKI episode after re-initiation of bortezomib. His renal function improved after glucocorticoid therapy and discontinuation of bortezomib. To our knowledge, this is the first report of a biopsy-proven AIN from bortezomib. Keywords: acute interstitial nephritis, bortezomib, C3 glomerulonephritis, monoclonal gammopathy, nephrotoxicity INTRODUCTION Acute interstitial nephritis (AIN) is one of the important causes of acute kidney injury (AKI) and the second leading cause of acute, intrinsic renal disease [1, 2], accounting for 0.5–2.6% of all renal biopsies. Its prevalence has been increasing in recent years [3]. The recognition of AIN is important since early discontinuation of offending agents may improve prognosis [3–5]. The causes of AIN include allergic reactions, infections and systemic autoimmune diseases such as sarcoidosis, © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
tubulointerstitial nephritis with uveitis syndrome and immunoglobulin G4-related disease (IgG4-RD) [3]. Allergic reactions to medications such as antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) continue to be the leading causes of AIN, accounting for more than two thirds of cases (2, 4, 7, 8). Bortezomib, a proteasome inhibitor, has been approved in the United States by the Food and Drug Administration (FDA) for treatment of multiple myeloma (MM) since 2003 [6] and has been increasingly used in a few glomerular diseases especially monoclonal gammopathy of renal significance (MGRS) [7]. We present a case of bortezomib-induced AIN in patients with C3 glomerulonephritis associated with a monoclonal gammopathy. To our knowledge, this is the first report of bortezomib-induced biopsy-proven AIN. CASE REPORT Clinical history and initial laboratory data A 47-year-old man presented to our institution for evaluation of uncontrolled hypertension and bilateral leg swelling. The patient had a prior history of painless gross hematuria and was evaluated in the emergency department a year prior to presentation to nephrology. At that time, he was found to have elevated serum creatinine (Cr) of 1.6 mg/dL (reference range 0.8–1.3 mg/dL). He was otherwise asymptomatic and was dismissed from the emergency department. One year later (a month prior to admission), the patient presented to the outside facility with bilateral leg edema and weight gain, and was found to have hypertension of 175/96 mmHg. Treatment with lisinopril, hydrochlorothiazide and furosemide was subsequently initiated. However, at 1-month follow-up, the patient developed worsening dyspnea and bilateral leg edema. 1225
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For this reason, the patient was referred and admitted to our hospital. He had a history of smoking but denied other significant medical problems, and there was no family history of kidney disease. On physical examination, he was hypertensive at 156/93 mmHg. There were bibasilar crackles on auscultation lung and 2+ pitting edema of the lower extremities; the physical examination was otherwise unremarkable. Laboratory testing, represented in Table 1, revealed serum Cr 1.7 mg/dL. Urinalysis showed hematuria [red blood cells (RBCs) >100/high power field (hpf )], 41–50 WBCs/hpf and 3+ protein. Dysmorphic RBCs were present. He underwent renal ultrasound with Doppler examination of the renal arteries, which demonstrated evidence of mildly increased echogenicity without
Laboratory testing
a At At first presentation AKI episode
b At second AKI episode
c
Serum creatinine (mg/dL) eGFR (mL/min/1.73 m2) Hb (g/dL) WBC (×109/L) Neutrophils (×109/L) Lymphocytes (×109/L) Eosinophil (×109/L) Platelet (×109/L) Serum albumin (g/dL) Proteinuria (g/24h) Urine eosinophil
1.7 43 9.9 8.5 5.9 1.7 0.2 257 2.5 12.5 N/A
3.0 23 8.6 8.4 6.5 1.1 0 474 2.9 12.7 N/A
1.7 43 12.0 8.0 5.9 1.2 0.1 266 2.6 11.8 N/A
3.2 21 9.5 10.6 8.5 0.9 0 206 2.9 N/A None
At 6.5 months
eGFR, estimated glomerular filtration rate; Hb, hemoglobin; WBC, white blood cell. a First AKI episode = 7 days after treatment with cyclophosphamide, bortezomib, dexamethasone and acyclovir. b Second AKI episode = 2 weeks after treatment with bortezomib and dexamethasone. c At 6.5 months = 1 month after re-initiating cyclophosphamide.
F I G U R E 1 : Line graph showing the evolution of serum creatinine and the timing of treatments. International System of Units conversion rates:
serum creatinine 1 mg/dL = 88.4 μmol/L.
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Table 1. Laboratory data
hydronephrosis. Chest X-ray showed no abnormalities. Proteinuria was measured at 12.5 g/24 h. Anti-nuclear antibody (ANA) was positive at 4.5 U (reference range 100/hpf ), 21–30 WBCs/ hpf and 3+ protein. Examination of the urine for eosinophils was negative. The patient underwent a repeat kidney biopsy for evaluation for his renal insufficiency.
F I G U R E 2 : Representative kidney biopsy findings showing C3 glomerulopathy and interstitial inflammation. Top panel shows C3 glomerulopathy. (A and B) Glomeruli shows mesangial and endocapillary hypercellularity, double contours along the capillary walls and lobular accentuation of the glomerular tufts (membranoproliferative pattern of injury) (A: Periodic acid Schiff stain ×10 and B: silver methenamine stain ×40). (C) Bright mesangial and capillary wall C3 staining (×40). Note (A) is biopsy specimen prior to bortezomib treatment and shows no significant interstitial inflammation. Bottom panel shows interstitial nephritis following bortezomib. (D and E) show interstitial nephritis with mostly mononuclear cell involving the cortex, and (F) evidence of small granuloma formation, arrow points to granuloma (D and E: hematoxylin and eosin, F: silver methenamine stain, D: ×20, E and F ×40).
Bortezomib-induced acute interstitial nephritis
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Diagnosis Kidney, needle biopsy: (i) C3 glomerulonephritis, with a membranoproliferative pattern of injury; (ii) AIN.
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Repeat kidney biopsy On light microscopy 12 glomeruli were present, of which 2 were globally sclerosed. The glomeruli showed mesangial and endocapillary hypercellularity with lobular accentuation of the glomerular capillary tufts. The glomerular capillary walls were thickened and double contour formation was noted. One cellular crescent was also noted. The interstitium showed a prominent interstitial infiltrate, with mostly mononuclear cells, and few eosinophils and neutrophils. Small non-necrotizing granulomas were present. Approximately 20% of the sample showed tubular atrophy and interstitial fibrosis. Immunofluorescence microscopy showed bright mesangial and capillary wall staining for C3, and trace glomerular staining IgG and kappa light chain staining of glomeruli and tubular basement membranes. Electron microscopy showed mesangial and few intramembranous and subendothelial capillary wall electron dense deposits. There was no evidence of light chain deposition disease by electron microscopy. Representative light and immunofluorescence microscopy findings are shown in Figure 2.
Clinical follow-up Due to a possibility of drug-induced AIN, trimethoprim/ sulfamethoxazole and pantoprazole were discontinued. Treatment with CyBorD was held. Methylprednisolone 1 g IV was administered and followed by prednisone 60 mg daily. His Cr eventually came down from a peak of around 5.0–1.7 mg/dL at 15 days after last dose of CyBorD treatment. At that time, CyBorD chemotherapy was resumed. Trimethoprim/sulfamethoxazole and pantoprazole were not restarted. Again, his Cr had increased to 3.0 mg/dL within 2 weeks of treatment. Thus, AIN related to his chemotherapy was suspected, and CyBorD chemotherapy was held. Methylprednisolone 500 mg IV was given and followed by oral prednisone 40 mg daily tapering as demonstrated in Figure 1. His kidney function continued to improve with serum Cr of 1.7 and 1.4 mg/dL at Day 12 and Day 21 after steroid treatment, respectively (Figure 1). However, his renal function declined at 2-month follow-up after last CyBorD treatment with Cr of 2.0 mg/dL. His urinalysis showed more active urinary sediment with over 100 red cells/high power field and red cell casts. Proteinuria was measured at 11.8 g/24 h. After a discussion with the patient regarding risks and benefits, the decision was made to start cyclophosphamide 100 mg daily (1 mg/kg per day). A month after cyclophosphamide treatment, the patient had improved kidney function with Cr of 1.7 mg/dL. Unfortunately, he developed cyclophosphamide-induced hepatitis. After discontinuation of cyclophosphamide, his hepatitis was improved, and the patient continued the treatment with only steroid tapering.
AIN is one of the important causes of AKI resulting from immune-mediated tubulointerstitial injury and medications continue to be the leading causes of AIN, accounting for more than two thirds of cases [2, 3, 8, 9]. Our case presentation, we present a case of bortezomib-induced biopsy-proven AIN, which, to our knowledge, has not previously been reported. Since FDA approval for bortezomib treatment for MM in 2003 [6], it has been increasingly used in a number of trials for treatment of antibody-mediated renal allograft rejection, AL amyloidosis, lupus nephritis, IgA nephropathy, idiopathic nephrotic syndrome and renal fibrosis [10–13]. To identify potential previously reported cases of AIN from bortezomib, the literature search of Embase, Medline and Cochrane through January 2015 was performed using the terms ‘bortezomib’, ‘velcade’ and ‘proteasome inhibitor’ combined with the terms ‘interstitial nephritis’ and ‘AIN’. Interestingly, a number of reports have stated that bortezomib is safe for the kidney. In patients with MM and Waldenstrom macroglobulinemia with evidence of interstitial inflammation, studies have shown improvement of kidney function after treatment with bortezomib [14–17]. In a mouse model, bortezomib was also shown to provide protection of podocyte ultrastructure [18]. Although bortezomib therapy has been described as a potential cause of drug-induced thrombotic microangiopathy in patients with MM [19–22], allergy related to bortezomib treatment has been reported to cause only mild reactions such as cutaneous involvement [23–25]. Conversely, in patients with MM treated with other agents such as lenalidomide, more severe allergic reactions including drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens– Johnson syndrome [25–28] as well as AIN [29] have been reported. Recently, interest has been focused on new proteasome inhibitors, such as carfilzomib for treatment of relapsed and refractory MM [11]. Notwithstanding the adverse effects of renal vasoconstriction after carfilzomib treatment [30], carfilzomib-induced AIN has never been described. In our case, the patient had biopsy-proven AIN after the treatment with bortezomib and subsequently developed recurrent AKI episode after re-exposure of bortezomib and after discontinuation of trimethoprim/sulfamethoxazole and PPIs. In addition, the patient’s kidney function after the re-initiation of cyclophosphamide was stable. Thus, his AIN was likely resulted from bortezomib treatment. In the literature review, Hunfeld et al. [31] previously reported a probable case of AIN after bortezomib treatment for MM. However, the kidney biopsy was not performed to confirm the diagnosis. In our case, the kidney biopsy also demonstrated the evidence of nonnecrotizing granulomas. Although AIN with granuloma formation has been commonly described in sarcoidosis, this finding has also been described in other forms of AIN including drug-induced AIN and infections related to specific pathogens [32] (Table 2). Cyclophosphamide is commonly used in combination with bortezomib in the treatment of MM [33]. However, it has not been reported as a potential cause of AIN. The fact that the
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Table 2. Causes of AIN with granulomas • Drug-induced acute interstitial nephritis • Infections: Mycobacterium, fungi (histoplasmosis, coccidiomycosis), bacteria (Brucella, Chlamydia), spirochetes (Francisella, Treponema) and parasites (Leishmania, Toxoplasma) • Systemic diseases ○ Sarcoidosis ○
Granulomatosis with polyangiitis (with crescentic glomerulonephritis)
patient was re-exposed to cyclophosphamide which resulted in further improvement in kidney rules out this agent as causing AIN in this patient. On the other hand, cyclophosphamide has been proposed as an alternative treatment for AIN [5, 34, 35]. Unlike cyclophosphamide, ifosfamide, a newly available analog of cyclophosphamide, has been shown to cause AIN [36]. Although rash, fever and eosinophilia are known as the triad for typical drug-induced AIN, such as methicillin, from a direct allergic response, the triad was reported only in 11% of cases [2]. In our case showed no component of the triad nor urine eosinophils. This is not a surprise since urine eosinophils perform poorly in cases of AIN [37]. Discontinuation of an offending agent is a universal recommendation for treatment of AIN. Although the benefits of glucocorticoid therapy are inconclusive, improvement in kidney function has been suggested by several uncontrolled reports [38, 39]. After discontinuation of bortezomib and glucocorticoid treatment, our patient’s kidney function improved. In conclusion, bortezomib is a potential cause of druginduced AIN. Frequent monitoring of renal function is required in patients who receive the combination of bortezomib with CYP3A4 metabolized drugs. To our knowledge, this is the first report of biopsy-proven AIN from bortezomib.
AUTHORS’ CONTRIBUTIONS All authors were involved and approved the final manuscript.
C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared.
REFERENCES 1. Bomback AS, Markowitz GS. Increased prevalence of acute interstitial nephritis: more disease or simply more detection? Nephrol Dial Transplant 2013; 28: 16–18 2. Praga M, Gonzalez E. Acute interstitial nephritis. Kidney Int 2010; 77: 956–961 3. Praga M, Sevillano A, Aunon P et al. Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. Nephrol Dial Transplant 2014; doi: 10.1093/ndt/gfu326 4. Goicoechea M, Rivera F, Lopez-Gomez JM. Increased prevalence of acute tubulointerstitial nephritis. Nephrol Dial Transplant 2013; 28: 112–115
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DISCUSSION
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Received for publication: 19.3.2015; Accepted in revised form: 16.4.2015
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24.
multiple myeloma: new drugs, old side effects. Cutan Ocul Toxicol 2014; 33: 1–6 Villarrubia B, Betlloch I, Mataix J et al. Bortezomib-associated rash: a new recognizable and avoidable side-effect. Br J Dermatol 2007; 156: 784–785 Reyes-Habito CM, Roh EK. Cutaneous reactions to chemotherapeutic drugs and targeted therapy for cancer: part II. Targeted therapy. J Am Acad Dermatol 2014; 71: 217 e1–217.e11; quiz 227–8 Boruah PK, Bolesta S, Shetty SM. Possible lenalidomide-induced StevensJohnson syndrome during treatment for multiple myeloma. Pharmacotherapy 2011; 31: 925 Shaaban H, Layne T, Guron G. A case of DRESS (drug reaction with eosinophilia and systemic symptoms) with acute interstitial nephritis secondary to lenalidomide. J Oncol Pharm Pract 2013; 20: 302–304 Sekiguchi Y, Shimada A, Imai H et al. Patient with refractory multiple myeloma developing eosinophilia after lenalidomide treatment and lung cancer 9 months later: case report and review of the literature. Indian J Hematol Blood Transfus 2014; 30(Suppl 1): 264–270 Muriithi AK, Leung N, Valeri AM et al. Biopsy-proven acute interstitial nephritis, 1993–2011: a case series. Am J Kidney Dis 2014; 64: 558–566 Wanchoo R, Khan S, Kolitz JE et al. Carfilzomib-related acute kidney injury may be prevented by N-acetyl-L-cysteine. J Oncol Pharm Pract 2014; doi: 10.1177/1078155214531804 Hunfeld N, Evers D, Van Hest R et al. Renal failure after bortezomib and erythromycin: a new interaction? [Dutch]. Pharm Weekbl 2010; 37: 162–163 Joss N, Morris S, Young B et al. Granulomatous interstitial nephritis. Clin J Am Soc Nephrol 2007; 2: 222–230 Kumar S, Flinn I, Richardson PG et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012; 119: 4375–4382 Zuliani E, Zwahlen H, Gilliet F et al. Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment. Clin Nephrol 2005; 64: 155–158 Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int 1989; 35: 1257–1270 Hill PA, Prince HM, Power DA. Tubulointerstitial nephritis following high-dose ifosfamide in three breast cancer patients. Pathology 2000; 32: 166–170 Muriithi AK, Nasr SH, Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. Clin J Am Soc Nephrol 2013; 8: 1857–1862 Rossert J. Drug-induced acute interstitial nephritis. Kidney Int 2001; 60: 804–817 Buysen JG, Houthoff HJ, Krediet RT et al. Acute interstitial nephritis: a clinical and morphological study in 27 patients. Nephrol Dial Transplant 1990; 5: 94–99
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5. Michel DM, Kelly CJ. Acute interstitial nephritis. J Am Soc Nephrol 1998; 9: 506–515 6. Adams J, Kauffman M. Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest 2004; 22: 304–311 7. Leung N, Bridoux F, Hutchison CA et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood 2012; 120: 4292–4295 8. Perazella MA, Markowitz GS. Drug-induced acute interstitial nephritis. Nature reviews. Nephrology 2010; 6: 461–470 9. Brewster UC, Perazella MA. Proton pump inhibitors and the kidney: critical review. Clin Nephrol 2007; 68: 65–72 10. Dubrey SW, Reece DE, Sanchorawala V et al. Bortezomib in a phase 1 trial for patients with relapsed AL amyloidosis: cardiac responses and overall effects. QJM 2011; 104: 957–970 11. Coppo R. Proteasome inhibitors in progressive renal diseases. Nephrol Dial Transplant 2014; 29(Suppl 1): i25–i30 12. Coppo R, Camilla R, Alfarano A et al. Upregulation of the immunoproteasome in peripheral blood mononuclear cells of patients with IgA nephropathy. Kidney Int 2009; 75: 536–541 13. Walsh RC, Alloway RR, Girnita AL et al. Proteasome inhibitor-based therapy for antibody-mediated rejection. Kidney Int 2012; 81: 1067–1074 14. Conway K, Shalaby T, Naylor E et al. Case report: incidental diagnosis of HIV-1 in an 82-year-old woman with acute kidney injury and multiple myeloma. HIV Med 2011; 12: 40 15. Nayer A, Green DF, Gonzalez-Suarez ML et al. Tubulointerstitial nephritis accompanying gamma-heavy chain deposition and gamma-heavy chain restricted plasma cells in the kidney. Iran J Kidney Dis 2014; 8: 417–423 16. Rio N, Nozomu K, Yuichiro O et al. Successful treatment with dexamethasone and bortezomib for proliferative glomerulonephritis with monoclonal IgG deposits in multiple myeloma. Nephrology 2014; 175, Abstr 19 17. Wikstrom SW, Catalanotti J. ARF: acute renal failure and a rare finding. J Gen Int Med 2011; S418, Abstr 26 18. Hainz N, Thomas S, Neubert K et al. The proteasome inhibitor bortezomib prevents lupus nephritis in the NZB/W F1 mouse model by preservation of glomerular and tubulointerstitial architecture. Nephron Exp Nephrol 2012; 120: e47–e58 19. Mehta N, Saxena A, Niesvizky R. Bortezomib-induced thrombotic thrombocytopaenic purpura. BMJ Case Rep 2012; doi: 10.1136/bcr-2012006461 20. Hofmeister CC, Jin M, Cataland SR et al. TTP disease course is independent of myeloma treatment and response. Am J Hematol 2010; 85: 304–306 21. Lechner K, Obermeier HL. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases. Medicine (Baltimore) 2012; 91: 195–205 22. Moore H, Romeril K. Multiple myeloma presenting with a fever of unknown origin and development of thrombotic thrombocytopenic purpura post-bortezomib. Intern Med J 2011; 41: 348–350 23. Patrizi A, Venturi M, Dika E et al. Cutaneous adverse reactions linked to targeted anticancer therapies bortezomib and lenalidomide for
The Bench-to-Bedside Transition Bortezomib-induced acute interstitial nephritis Wisit Cheungpasitporn1, Nelson Leung1,2, S. Vincent Rajkumar2, Lynn D. Cornell3, Sanjeev Sethi3, Andrea Angioi1 and Fernando C. Fervenza1 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA, 2Division of Hematology, Mayo Clinic, Rochester, MN, USA
and 3Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
Correspondence and offprint requests to: Fernando C. Fervenza; E-mail: [email protected]
A B S T R AC T Acute interstitial nephritis (AIN) is one of the important causes of acute kidney injury (AKI) resulting from inflammatory tubulointerstitial injury induced by medications, infections and systemic diseases. Bortezomib has been increasingly used especially in renal related indications such as multiple myeloma and monoclonal gammopathy of renal significance. Severe allergic reactions from bortezomib treatment including AIN have not been described in the literature. We report a 47-year-old white man who developed biopsy-proven allergic AIN after treatment with bortezomib for his C3 glomerulonephritis. The patient’s kidney function improved after treatment with glucocorticoid therapy and discontinuation of bortezomib, but worsened with recurrent AKI episode after re-initiation of bortezomib. His renal function improved after glucocorticoid therapy and discontinuation of bortezomib. To our knowledge, this is the first report of a biopsy-proven AIN from bortezomib. Keywords: acute interstitial nephritis, bortezomib, C3 glomerulonephritis, monoclonal gammopathy, nephrotoxicity INTRODUCTION Acute interstitial nephritis (AIN) is one of the important causes of acute kidney injury (AKI) and the second leading cause of acute, intrinsic renal disease [1, 2], accounting for 0.5–2.6% of all renal biopsies. Its prevalence has been increasing in recent years [3]. The recognition of AIN is important since early discontinuation of offending agents may improve prognosis [3–5]. The causes of AIN include allergic reactions, infections and systemic autoimmune diseases such as sarcoidosis, © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
tubulointerstitial nephritis with uveitis syndrome and immunoglobulin G4-related disease (IgG4-RD) [3]. Allergic reactions to medications such as antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) continue to be the leading causes of AIN, accounting for more than two thirds of cases (2, 4, 7, 8). Bortezomib, a proteasome inhibitor, has been approved in the United States by the Food and Drug Administration (FDA) for treatment of multiple myeloma (MM) since 2003 [6] and has been increasingly used in a few glomerular diseases especially monoclonal gammopathy of renal significance (MGRS) [7]. We present a case of bortezomib-induced AIN in patients with C3 glomerulonephritis associated with a monoclonal gammopathy. To our knowledge, this is the first report of bortezomib-induced biopsy-proven AIN. CASE REPORT Clinical history and initial laboratory data A 47-year-old man presented to our institution for evaluation of uncontrolled hypertension and bilateral leg swelling. The patient had a prior history of painless gross hematuria and was evaluated in the emergency department a year prior to presentation to nephrology. At that time, he was found to have elevated serum creatinine (Cr) of 1.6 mg/dL (reference range 0.8–1.3 mg/dL). He was otherwise asymptomatic and was dismissed from the emergency department. One year later (a month prior to admission), the patient presented to the outside facility with bilateral leg edema and weight gain, and was found to have hypertension of 175/96 mmHg. Treatment with lisinopril, hydrochlorothiazide and furosemide was subsequently initiated. However, at 1-month follow-up, the patient developed worsening dyspnea and bilateral leg edema. 1225
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1
For this reason, the patient was referred and admitted to our hospital. He had a history of smoking but denied other significant medical problems, and there was no family history of kidney disease. On physical examination, he was hypertensive at 156/93 mmHg. There were bibasilar crackles on auscultation lung and 2+ pitting edema of the lower extremities; the physical examination was otherwise unremarkable. Laboratory testing, represented in Table 1, revealed serum Cr 1.7 mg/dL. Urinalysis showed hematuria [red blood cells (RBCs) >100/high power field (hpf )], 41–50 WBCs/hpf and 3+ protein. Dysmorphic RBCs were present. He underwent renal ultrasound with Doppler examination of the renal arteries, which demonstrated evidence of mildly increased echogenicity without
Laboratory testing
a At At first presentation AKI episode
b At second AKI episode
c
Serum creatinine (mg/dL) eGFR (mL/min/1.73 m2) Hb (g/dL) WBC (×109/L) Neutrophils (×109/L) Lymphocytes (×109/L) Eosinophil (×109/L) Platelet (×109/L) Serum albumin (g/dL) Proteinuria (g/24h) Urine eosinophil
1.7 43 9.9 8.5 5.9 1.7 0.2 257 2.5 12.5 N/A
3.0 23 8.6 8.4 6.5 1.1 0 474 2.9 12.7 N/A
1.7 43 12.0 8.0 5.9 1.2 0.1 266 2.6 11.8 N/A
3.2 21 9.5 10.6 8.5 0.9 0 206 2.9 N/A None
At 6.5 months
eGFR, estimated glomerular filtration rate; Hb, hemoglobin; WBC, white blood cell. a First AKI episode = 7 days after treatment with cyclophosphamide, bortezomib, dexamethasone and acyclovir. b Second AKI episode = 2 weeks after treatment with bortezomib and dexamethasone. c At 6.5 months = 1 month after re-initiating cyclophosphamide.
F I G U R E 1 : Line graph showing the evolution of serum creatinine and the timing of treatments. International System of Units conversion rates:
serum creatinine 1 mg/dL = 88.4 μmol/L.
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Table 1. Laboratory data
hydronephrosis. Chest X-ray showed no abnormalities. Proteinuria was measured at 12.5 g/24 h. Anti-nuclear antibody (ANA) was positive at 4.5 U (reference range 100/hpf ), 21–30 WBCs/ hpf and 3+ protein. Examination of the urine for eosinophils was negative. The patient underwent a repeat kidney biopsy for evaluation for his renal insufficiency.
F I G U R E 2 : Representative kidney biopsy findings showing C3 glomerulopathy and interstitial inflammation. Top panel shows C3 glomerulopathy. (A and B) Glomeruli shows mesangial and endocapillary hypercellularity, double contours along the capillary walls and lobular accentuation of the glomerular tufts (membranoproliferative pattern of injury) (A: Periodic acid Schiff stain ×10 and B: silver methenamine stain ×40). (C) Bright mesangial and capillary wall C3 staining (×40). Note (A) is biopsy specimen prior to bortezomib treatment and shows no significant interstitial inflammation. Bottom panel shows interstitial nephritis following bortezomib. (D and E) show interstitial nephritis with mostly mononuclear cell involving the cortex, and (F) evidence of small granuloma formation, arrow points to granuloma (D and E: hematoxylin and eosin, F: silver methenamine stain, D: ×20, E and F ×40).
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Diagnosis Kidney, needle biopsy: (i) C3 glomerulonephritis, with a membranoproliferative pattern of injury; (ii) AIN.
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Repeat kidney biopsy On light microscopy 12 glomeruli were present, of which 2 were globally sclerosed. The glomeruli showed mesangial and endocapillary hypercellularity with lobular accentuation of the glomerular capillary tufts. The glomerular capillary walls were thickened and double contour formation was noted. One cellular crescent was also noted. The interstitium showed a prominent interstitial infiltrate, with mostly mononuclear cells, and few eosinophils and neutrophils. Small non-necrotizing granulomas were present. Approximately 20% of the sample showed tubular atrophy and interstitial fibrosis. Immunofluorescence microscopy showed bright mesangial and capillary wall staining for C3, and trace glomerular staining IgG and kappa light chain staining of glomeruli and tubular basement membranes. Electron microscopy showed mesangial and few intramembranous and subendothelial capillary wall electron dense deposits. There was no evidence of light chain deposition disease by electron microscopy. Representative light and immunofluorescence microscopy findings are shown in Figure 2.
Clinical follow-up Due to a possibility of drug-induced AIN, trimethoprim/ sulfamethoxazole and pantoprazole were discontinued. Treatment with CyBorD was held. Methylprednisolone 1 g IV was administered and followed by prednisone 60 mg daily. His Cr eventually came down from a peak of around 5.0–1.7 mg/dL at 15 days after last dose of CyBorD treatment. At that time, CyBorD chemotherapy was resumed. Trimethoprim/sulfamethoxazole and pantoprazole were not restarted. Again, his Cr had increased to 3.0 mg/dL within 2 weeks of treatment. Thus, AIN related to his chemotherapy was suspected, and CyBorD chemotherapy was held. Methylprednisolone 500 mg IV was given and followed by oral prednisone 40 mg daily tapering as demonstrated in Figure 1. His kidney function continued to improve with serum Cr of 1.7 and 1.4 mg/dL at Day 12 and Day 21 after steroid treatment, respectively (Figure 1). However, his renal function declined at 2-month follow-up after last CyBorD treatment with Cr of 2.0 mg/dL. His urinalysis showed more active urinary sediment with over 100 red cells/high power field and red cell casts. Proteinuria was measured at 11.8 g/24 h. After a discussion with the patient regarding risks and benefits, the decision was made to start cyclophosphamide 100 mg daily (1 mg/kg per day). A month after cyclophosphamide treatment, the patient had improved kidney function with Cr of 1.7 mg/dL. Unfortunately, he developed cyclophosphamide-induced hepatitis. After discontinuation of cyclophosphamide, his hepatitis was improved, and the patient continued the treatment with only steroid tapering.
AIN is one of the important causes of AKI resulting from immune-mediated tubulointerstitial injury and medications continue to be the leading causes of AIN, accounting for more than two thirds of cases [2, 3, 8, 9]. Our case presentation, we present a case of bortezomib-induced biopsy-proven AIN, which, to our knowledge, has not previously been reported. Since FDA approval for bortezomib treatment for MM in 2003 [6], it has been increasingly used in a number of trials for treatment of antibody-mediated renal allograft rejection, AL amyloidosis, lupus nephritis, IgA nephropathy, idiopathic nephrotic syndrome and renal fibrosis [10–13]. To identify potential previously reported cases of AIN from bortezomib, the literature search of Embase, Medline and Cochrane through January 2015 was performed using the terms ‘bortezomib’, ‘velcade’ and ‘proteasome inhibitor’ combined with the terms ‘interstitial nephritis’ and ‘AIN’. Interestingly, a number of reports have stated that bortezomib is safe for the kidney. In patients with MM and Waldenstrom macroglobulinemia with evidence of interstitial inflammation, studies have shown improvement of kidney function after treatment with bortezomib [14–17]. In a mouse model, bortezomib was also shown to provide protection of podocyte ultrastructure [18]. Although bortezomib therapy has been described as a potential cause of drug-induced thrombotic microangiopathy in patients with MM [19–22], allergy related to bortezomib treatment has been reported to cause only mild reactions such as cutaneous involvement [23–25]. Conversely, in patients with MM treated with other agents such as lenalidomide, more severe allergic reactions including drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens– Johnson syndrome [25–28] as well as AIN [29] have been reported. Recently, interest has been focused on new proteasome inhibitors, such as carfilzomib for treatment of relapsed and refractory MM [11]. Notwithstanding the adverse effects of renal vasoconstriction after carfilzomib treatment [30], carfilzomib-induced AIN has never been described. In our case, the patient had biopsy-proven AIN after the treatment with bortezomib and subsequently developed recurrent AKI episode after re-exposure of bortezomib and after discontinuation of trimethoprim/sulfamethoxazole and PPIs. In addition, the patient’s kidney function after the re-initiation of cyclophosphamide was stable. Thus, his AIN was likely resulted from bortezomib treatment. In the literature review, Hunfeld et al. [31] previously reported a probable case of AIN after bortezomib treatment for MM. However, the kidney biopsy was not performed to confirm the diagnosis. In our case, the kidney biopsy also demonstrated the evidence of nonnecrotizing granulomas. Although AIN with granuloma formation has been commonly described in sarcoidosis, this finding has also been described in other forms of AIN including drug-induced AIN and infections related to specific pathogens [32] (Table 2). Cyclophosphamide is commonly used in combination with bortezomib in the treatment of MM [33]. However, it has not been reported as a potential cause of AIN. The fact that the
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Table 2. Causes of AIN with granulomas • Drug-induced acute interstitial nephritis • Infections: Mycobacterium, fungi (histoplasmosis, coccidiomycosis), bacteria (Brucella, Chlamydia), spirochetes (Francisella, Treponema) and parasites (Leishmania, Toxoplasma) • Systemic diseases ○ Sarcoidosis ○
Granulomatosis with polyangiitis (with crescentic glomerulonephritis)
patient was re-exposed to cyclophosphamide which resulted in further improvement in kidney rules out this agent as causing AIN in this patient. On the other hand, cyclophosphamide has been proposed as an alternative treatment for AIN [5, 34, 35]. Unlike cyclophosphamide, ifosfamide, a newly available analog of cyclophosphamide, has been shown to cause AIN [36]. Although rash, fever and eosinophilia are known as the triad for typical drug-induced AIN, such as methicillin, from a direct allergic response, the triad was reported only in 11% of cases [2]. In our case showed no component of the triad nor urine eosinophils. This is not a surprise since urine eosinophils perform poorly in cases of AIN [37]. Discontinuation of an offending agent is a universal recommendation for treatment of AIN. Although the benefits of glucocorticoid therapy are inconclusive, improvement in kidney function has been suggested by several uncontrolled reports [38, 39]. After discontinuation of bortezomib and glucocorticoid treatment, our patient’s kidney function improved. In conclusion, bortezomib is a potential cause of druginduced AIN. Frequent monitoring of renal function is required in patients who receive the combination of bortezomib with CYP3A4 metabolized drugs. To our knowledge, this is the first report of biopsy-proven AIN from bortezomib.
AUTHORS’ CONTRIBUTIONS All authors were involved and approved the final manuscript.
C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared.
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THE BENCH-TO-BEDSIDE TRANSITION
DISCUSSION
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Received for publication: 19.3.2015; Accepted in revised form: 16.4.2015
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Bortezomib-induced acute interstitial nephritis
24.
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