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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2014  |  Volume : 25  |  Issue : 1  |  Page : 121-125
Acute renal failure and severe thrombocytopenia associated with metamizole


1 Nephrology Section, Hospital General de Elche, Alicante, Spain
2 Hematology Section, Hospital General de Elche, Alicante, Spain

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Date of Web Publication7-Jan-2014
 

   Abstract 

Metamizole or dipyrone is a pyrazolone derivative that belongs to the non-steroidal anti-inflammatory drugs. Its main side-effect is hematological toxicity. Thrombocytopenia due to metamizole is rare and is usually associated with the involvement of the two other blood series. Drug-induced thrombocytopenia is more frequently related to immune mechanisms, and the diag­nosis is still largely made by exclusion of other causes and by correlation of timing of thrombocytopenia with the administration of drug. Metamizole may cause acute renal failure due to hemodynamic renal failure/acute tubular necrosis and/or acute tubulointerstitial nephritis. We report a case of acute renal failure and severe thrombocytopenia after metamizole. As far as we know, this combination of adverse effects from this drug has not been reported previously.

How to cite this article:
Redondo-Pachon MD, Enríquez R, Sirvent AE, Millan I, Romero A, Amorós F. Acute renal failure and severe thrombocytopenia associated with metamizole. Saudi J Kidney Dis Transpl 2014;25:121-5

How to cite this URL:
Redondo-Pachon MD, Enríquez R, Sirvent AE, Millan I, Romero A, Amorós F. Acute renal failure and severe thrombocytopenia associated with metamizole. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2018 Dec 19];25:121-5. Available from: http://www.sjkdt.org/text.asp?2014/25/1/121/124524

   Introduction Top


Metamizole or dipyrone is a pyrazolone deri­vative that belongs to the non-steroidal anti-inflammatory drugs (NSAIDs), frequently used due to its analgesic and antipyretic properties. [1] However, this drug has not been mar­keted for years in several countries due to its severe side-effects, mainly related to hematological toxicity. In fact, since 1977 in the United States, the FDA has banned its use due to several fatal cases of agranulocytosis. In other countries (Spain included), it is still considered as a first-line analgesic despite the possible adverse effects described, such as agranulocytosis and aplastic anemia, skin aller­gic reactions, toxic epidermal necrolysis, oligohydramnios and severe arterial hypotension.

Acute renal failure, as tubulointerstitial neph­ritis or acute tubular necrosis, after metamizole is known; as a matter of fact, in a study, the incidence of acute interstitial nephritis for metamizole was 10.48 cases per 10,000 patient-years. [2]

We report a case of acute renal failure and severe thrombocytopenia after metamizole in­take. To the best of our knowledge, this com­bination of adverse effects from this drug has not been reported previously.


   Case Report Top


A 70-year-old male was admitted to the cli­nical ward due to nausea and malaise for 48 h.

His medical history includes an episode of acute renal failure that happened ten months prior to his current admission. He was diag­nosed with acute tubular necrosis by renal biopsy probably due to ibuprofen intake and his renal function recovered partially (creatinine 1.83 mg/dL, glomerular filtration rate estimated by MDRD formula 37.77 mL/min/ 1.73 m 2 ). Also, the patient was diagnosed with monoclonal gammopathy of undetermined sig­nificance and hypertension controlled with amlodipine 5 mg/day and furosemide 20 mg/ day. One month prior to admission, his creatinine was 1.63 mg/dL.

During the 15 days prior to admission, the patient took metamizole (nine 575 mg cap­sules) because of low back pain; the last dose he took was four days before admission. He had never taken metamizole before and he de­nied having fever, nausea, vomiting or diarrhea.

Physical examination showed BP 180/90 mm Hg; afebrile, no edema, skin lesions or organomegaly. Labotory tests on admission are shown in [Table 1].
Table 1: Test results on admission.

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C3-C4, ANCA, anti-GBM, ANA, anti-DNA, anticardiolipin antibodies, lupus anticoagulant and cryoglobulins were all normal/negative. Direct Coombs test was negative and schistocytes were not detected in peripheral blood. Viral serology for HBV, HCV and HIV was negative; serology for CMV, EBV and parvovirus B19 revealed past exposure. The blood monoclonal component detected ten months ago remained stable and unchanged.

Renal ultrasound showed a right kidney of 11.1 cm and a left kidney of 10.5 cm, with in­creased cortical echogenicity. Bone marrow aspirate disclosed normal cell appearance (2% plasma cells) and predominance of megakaryopoietic precursors, point to peripheral thrombocytopenia. No lytic lesions were seen on spi­nal magnetic resonance imaging.

Acute renal failure and immune thrombocytopenia in association with metamizole were considered. Empirical treatment with steroids was initiated; the patient was treated with intravenous methylprednisolone 500 mg fol­lowed by oral prednisone (1 mg/kg/day for two weeks), which was tapered until withdra­wal over eight weeks.

The evolution of acute renal failure and thrombocytopenia are shown in [Figure 1] and [Figure 2].
Figure 1: Renal function follow-up.

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Figure 2: Thrombocytopenia follow-up.

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Ten days after admission, the patient reco­vered his platelet level and renal function returned to baseline. Diuresis was maintained throughout admission. Ten months later, creatinine was 1.7 mg/dL, thrombocytopenia had not recurred and the patient remained on amlodipine regularly and furosemide as and when needed.


   Discussion Top


Metamizole is included in the NSAIDs. [3] Unlike "classic" NSAIDs, metamizole has a potent analgesic with low anti-inflammatory effect. The mechanism of action for meta-mizole is controversial. It was initially des­cribed as a potent prostaglandin inhibitor in brain tissue, but it has recently been described as a selective inhibitor of enzyme COX3, a COX 1 variant. [4] Other authors indicate that metamizole acts at the peripheral, but not cen­tral, level through a mechanism independent from the endogenous opioid system. [5] These mechanisms that differ from classic NSAIDs lead some authors to classify metamizole out­side this group.

Agranulocytosis is the most common blood dyscrasia secondary to this drug. However, thrombocytopenia is extremely rare and is usually associated with the involvement of the two other series. [6] From a total of 66 cases of metamizole-associated blood dyscrasia, Hedenmalm et al found only four cases of thrombocytopenia; two of them with agranulocytosis and the other two with pancytopenia. [7]

Thrombocytopenia secondary to drugs may be seen as a part of pancytopenia due to bone marrow suppression. More frequently, isolated drug-induced thrombocytopenia is related to immune mechanisms (hapten-dependent anti­bodies, anti-drug-glycoprotein complex anti­bodies, autoantibodies, specific antibodies to drugs and antibodies to immune complexes). [8] Thrombocytopenia occurs within one to two weeks after drug exposure, and there is no reliable antibody testing. Other negative re­sults and the evident temporal association with metamizole support this drug's pathogenic role in our patient. According to George and Aster, [9] the level of evidence in this case would be probable. To consider a definitive level, these authors require the recurrence of thrombocytopenia upon re-exposure to the drug. We do not consider it through our patient's history given.

Steroid's usefulness in drug-associated immune thrombocytopenia has not been established. However, some authors recommend steroids initially given the possibility of idiopathic thrombocytopenic purpura. Immunoallergic in­terstitial nephritis was also suspected in this patient.

Metamizole may cause acute renal failure due to hemodynamic renal failure/acute tubular nec­rosis, related to the suppression of vasodilating prostaglandins and acute tubulointerstitial neph­ritis of immunoallergic basis. There are several isolated cases, [10],[11] but the largest series has been recently published by Hassan et al, [12] who describe 11 cases of acute renal failure asso­ciated with this drug. The clinical picture appears one week after taking the drug. It manifests as acute non-oliguric renal failure and proteinuria below 1 g/24 h; no patient re­quired renal replacement therapy and renal function recovered spontaneously within 7-10 days. A renal biopsy was performed in only one patient.

As with other NSAIDs, metamizole-induced acute interstitial nephritis is usually not accom­panied by systemic manifestations such as fe­ver or skin lesions, but it has a shorter latency period and, usually, there is no significant proteinuria. [1] Even though metamizole-induced acute renal failure has good prognosis, dialysis has been necessary in isolated cases. [1] In this patient, relatively mild sediment favored acute tubular necrosis, but the presence of thrombocytopenia suggested the possibility of immune tubulointerstitial nephritis; therefore, we deci­ded to treat the patient with steroids. On the other hand, the coexistence of both renal le­sions cannot be ruled out. A renal biopsy was not performed initially due to thrombocytopenia and later because the renal status improved. Renal biopsy is often not performed in cases of acute renal failure by metamizol and, in fact, some authors consider that it is not necessary in this setting. [12]

During his first admission, our patient was diagnosed with monoclonal gammopathy of undetermined significance, and every attempt was made to rule out multiple myeloma: Quantification of bone marrow plasma cells was less than 10%, monoclonal peak values in blood or urine remained stable and lytic bone lesions were absent. The clinical course does not suggest either multiple myeloma or other nephropathy associated with monoclonal gammopathy.

In conclusion, this would probably be the first case reported in the literature having a combination of acute renal failure and severe thrombocytopenia due to metamizole. Addi­tionally, our patient illustrates that in a case of acute renal failure with thrombocytopenia, in addition to systemic conditions (infection, sys­temic lupus erythomatosus/antiphospholipid syn­drome, thrombotic microangiopathy), pharma­cological toxicity should also be considered.

 
   References Top

1.Berruti V, Salvidio G, Saffioti S, et al. Norami-dopyrine (Metamizol) and acute interstitial nephritis. Nephrol Dial Transplant 1998;13: 2110-2.  Back to cited text no. 1
[PUBMED]    
2.Garcia M, Saracho R, Jaio N, Vrotsoukanari K, Aguirre C. Inadequate drug prescription and the rise in drug-induced acute tubulointerstitial nephritis incidence. NDT Plus 2010;3:555-7.  Back to cited text no. 2
    
3.Rang HP, Dale MM, Ritter JM, Moore P. Pharmacology 2006. Churchill Livingstone: London; 6th edn.  Back to cited text no. 3
    
4.Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/anti­pyretic drugs: Cloning, structure, and expres­sion. Proc Natl Acad Sci USA 2002;99:13926-31.  Back to cited text no. 4
[PUBMED]    
5.Hinz B, Cheremina O, Bachmakov J, et al. Dipyrone elicits substantial inhibition of peri­pheral cyclooxygenases in humans: New insights into the pharmacology of an old analgesic. FASEB J 2007;21:2343-51.  Back to cited text no. 5
[PUBMED]    
6.Montoya GA, Vaca C, Parra MF. Adverse events associated with tramadol and dipirona admi­nistration in a level III hospital. Biomedica 2009;29:369-81.  Back to cited text no. 6
[PUBMED]    
7.Hedenmalm K, Spigset O. Agranulocytosis and other blood discrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol 2002;58: 265-74.  Back to cited text no. 7
[PUBMED]    
8.Kenny B, Stack G. Drug-induced immune thrombocytopenia. Arch Pathol Lab Med 2009;133: 309-14.  Back to cited text no. 8
    
9.George JN, Aster RH. Drug-induced thrombocytopenia: Pathogenesis, evaluation, and management. Hematology Am Soc Hematol Educ Program 2009:153-8.  Back to cited text no. 9
[PUBMED]    
10.Peces R, Pedrajas A. Non-oliguric acute renal failure and abortion induced by metamizol overdose. Nephrol Dial Transplant 2004;19:2683-5.  Back to cited text no. 10
[PUBMED]    
11.Sánchez de la Nieta MD, Rivera F, De la Torre M, et al. Acute renal failure and oligohydramnios induced by magnesium dypirone (metamizol) in a pregnant woman. Nephrol Dial Transplant 2003;18:1679-80.  Back to cited text no. 11
    
12.Hassan K, Khazim K, Hassan F, Hassan S. Acute kidney injury associated with meta-mizole sodium ingestion. Ren Fail 2011;33: 544-7.  Back to cited text no. 12
[PUBMED]    

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Correspondence Address:
Maria Dolores Redondo-Pachon
Nephrology Section, Hospital General Universitario de Elche, Alicante
Spain
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DOI: 10.4103/1319-2442.124524

PMID: 24434395

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