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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2016  |  Volume : 27  |  Issue : 1  |  Page : 157-160
Use of high-dose prednisolone to overcome rifampicin-induced corticosteroid non-responsiveness in childhood nephrotic syndrome


Department of Pediatric Disciplines, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, India

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Date of Web Publication15-Jan-2016
 

   Abstract 

Inducing remission in nephrotic children on anti-tubercular therapy is difficult due to the increased metabolism of prednisolone induced by rifampicin. We report a child with nephrotic syndrome treated successfully with an increased dose of steroids without discontinuing anti-tubercular therapy.

How to cite this article:
Barman H, Dass R, Duwarah S G. Use of high-dose prednisolone to overcome rifampicin-induced corticosteroid non-responsiveness in childhood nephrotic syndrome. Saudi J Kidney Dis Transpl 2016;27:157-60

How to cite this URL:
Barman H, Dass R, Duwarah S G. Use of high-dose prednisolone to overcome rifampicin-induced corticosteroid non-responsiveness in childhood nephrotic syndrome. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Feb 28];27:157-60. Available from: http://www.sjkdt.org/text.asp?2016/27/1/157/174198

   Introduction Top


Nephrotic syndrome (NS) is common in children, and nephrotic children are susceptible to infections due to immunological changes caused by the disease and also secondary to immunosuppressive therapy. Common infections are bacterial and viral, but tuberculosis is also of concern, especially in developing countries such as India. [1],[2] Treating children with NS and tuberculosis is a challenge and such patients do not do well on standard steroid doses. [2] This is because rifampicin is a potent inducer of the P450 oxidative system, which metabolizes prednisolone. [3] However, there are no guidelines on how to manage such cases in the setting of NS. We present a child with NS and tuberculosis who was successfully treated by simply increasing the steroid dose without withdrawal of rifampicin-based DOTS anti-tubercular therapy (ATT). The relevant literature is reviewed in brief and the approach to such a case is critically appraised.


   Case Report Top


A six-year-old girl presented with a first episode of swelling of the whole body and decreased urine output. There was no history of gross hematuria. On examination, there was anasarca, normal blood pressure and upper respiratory tract infection. Investigations are summarized in [Table 1]. She had a positive contact history of tuberculosis. The child was diagnosed as having NS with concomitant disseminated tuberculosis and started on DOTS. She was started on prednisolone (2 mg/kg/ day) because of the presence of serositis. The child was discharged on request before remission was achieved. She did not go into remission despite four weeks of full-dose steroids with good compliance. The course is illustrated in [Figure 1]. This met the definition of resistance, but the clinical profile of the patient did not suggest resistance. The child did not develop cushingoid features even after four weeks of daily steroids and hence a possibility of pseudoresistance was considered and drug interaction was considered to be the cause. We decided to defer renal biopsy to six weeks as a non-responsiveness secondary to drug interaction rather than true resistance was suspected at this time. The standard dose of steroids was continued. Pglycoproteins (P-gp), a product of multi resistance gene-1 (MDR-1) and interleukin-2 receptor (sIL2R) as inflammatory biomakers have recently been suggested for prediction of steroid response and could have been utilized at this point, but such facilities were not available to us; the facility to monitor prednisolone levels was also not available. In the meantime, options were explored. She returned for follow-up in the fifth week with gross edema when she was admitted for the treatment of edema and for renal biopsy subsequently. The steroid dose was increased by 1.5-times (3 mg/kg) empirically She went into remission in the next 10 days. Considering the starting dose of 2 mg/kg/day of prednisolone as inadequate, we decided to prolong the steroid course at 3 mg/kg/day for three more weeks (at least 4 weeks of "adequate" daily therapy). She was followed-up on a weekly basis for features of toxicity. On completion of four weeks of therapy with 3 mg/kg/day of steroids, further treatment was continued for six weeks with alternate-day prednisolone at a dose of 2 mg/kg (i.e., 1.5-times 1.5 mg/kg) followed by abrupt stoppage of the drug. She is on followup for 1.5 years since stopping the drug and has had no relapse till now.
Figure 1: Steroid response related to time in the study patient.

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Table 1: Summary of investigations in the study patient.

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   Discussion Top


Edwards et al made the first description of a reduction in the pharmacological half-life of cortisol in a patient with Addison's disease who was being treated with rifampicin. The reduced half-life of cortisol returned to normal when rifampicin was stopped. [4] Hendrickse at al reported a child with NS in whom ATT was used. [5] This child with minimal change NS showed no response to 2 mg/kg steroids at four weeks. They documented a decreased half-life of prednisolone in this child, which improved after discontinuation of ATT, and the child went into remission and continued to respond to steroids. A similar case has also been described from India. [6]

The impact of this interaction is not limited to NS. Progressive loss of renal allograft function can occur due to increased degradation of methyl prednisolone during treatment with rifampicin. However, there are no guidelines to manage this problem.

We may have the following potential solutions:

  1. Withdraw ATT:
    Similar approaches were adopted by Edwards et al and Verma et al. [4],[6] However, that is not possible in all cases as the co-existing tuberculosis merits treatment.
  2. Withdraw rifampicin with modified ATT:
    ATT containing quinolone to replace rifampicin as has been used in other circumstances can be adopted in NS. [7] However, it makes the regimen costlier, especially because the child gets dropped out of the DOTS regimen. Moreover, efficacy of such regimens is yet to be proved.
  3. Pulse methyl prednisolone:
    French pediatric nephrologists use pulse methyl prednisolone before defining steroid resistance. [8] This approach would probably surmount the increased steroid metabolism and induce remission. However, it would again relapse if the "increased need" of steroids is not recognized and not maintained with "adequate" steroid dose.
  4. Increase dose of prednisolone to compensate for increased metabolism:
    A similar approach has been adopted by Buffington in a renal transplant recipient. [9] A twoto three-fold dose increment is suggested to com-pensate for the increased metabolism for patients on rifampin. [3] However, the increment in dose required for patients with NS is not clear, and we did not come across any reports of such a high dose being used in NS. In our case, we adopted this approach and empirically increased the steroid dose to 1.5 times. This conservative modest dose elevation was decided based on lack of previous published experience as well as the pharmacokinetic findings of Lee et al. [10]


It is known that 3% of nephrotic children respond after four weeks. There is a very strong predictive value of days taken to respond and the future course. [11] Our patient was followedup for one year and she did not have any relapse during that period. Therefore, it was the dose and not the duration that worked for this child. To the best of our knowledge and belief, ours is the first child with NS to be treated successfully with an elevated dose of steroids without discontinuing ATT.

All the previous reports of ripampicin-prednisolone drug interaction in NS have been managed by withdrawal of rifampicin. This is not possible in all circumstances and questions the very decision of introducing ATT in the case. We demonstrate the safety and efficacy of a new strategy to overcome such pseudoresistance by increasing the dose of prednisolone. However, the exact dose of steroids for an optimal response is a question yet to be answered.

Conflict of interest: None declared.

 
   References Top

1.
Gulati S, Kher V, Gulati K, Arora P, Gujral R. Tuberculosis in childhood nephrotic syndrome in India. Pediatr Nephrol 1997;11:695-8.  Back to cited text no. 1
    
2.
Tambunan T, Dewanti A, Madiyono B, Rahayoe NN. Pulmonary tuberculosis in childhood nephrotic syndrome. Paediatr Indones 2001;41:106-10.  Back to cited text no. 2
    
3.
Finch CK, Chrisman CR, Baciewicz AM, Self TH. Rifampin and rifabutin drug interactions: An update. Arch Intern Med 2002;162:985-92.  Back to cited text no. 3
    
4.
Edwards OM, Courtenay-Evans RJ, Galley JM, Hunter J, Tait AD. Changes in cortisol metabolism following rifampicin therapy. Lancet 1974;2:548-51.  Back to cited text no. 4
[PUBMED]    
5.
Hendrickse W, McKiernan J, Pickup M, Lowe J. Rifampicin-induced non-responsiveness to corticosteroid treatment in nephrotic syndrome. Br Med J 1979;1:306.  Back to cited text no. 5
    
6.
Verma M, Singh T, Chhatwal J, Saini V, Pawar B. Rifampicin induced steroid unresponsiveness in nephrotic syndrome. Indian Pediatr 1994; 31:1437.  Back to cited text no. 6
[PUBMED]    
7.
Yoon HE, Jeon YJ, Chung HW, et al. Safety and efficacy of a quinolone-based regimen for treatment of tuberculosis in renal transplant recipients. Transplant Proc 2012;44:730-3.  Back to cited text no. 7
    
8.
Hoyer PF, Vester U, Becker JU. Steroid resistant nephrotic syndrome. In: Geary DE, Schaefer F, eds. Comprehensive Pediatric Nephrology. 1st ed. Philadelphia: Mosby Elsevier; 2008. p. 257-66.  Back to cited text no. 8
    
9.
Buffington GA, Dominguez JH, Piering WF, Hebert LA, Kauffman HM Jr., Lemann J Jr. Interaction of rifampin and glucocorticoids. Adverse effect on renal allograft function. JAMA 1976;236:1958-60.  Back to cited text no. 9
    
10.
Lee KH, Shin JG, Chong WS, et al. Time course of the changes in prednisolone pharmacokinetics after co-administration or discontinuation of rifampin. Eur J Clin Pharmacol 1993;45:287-9.  Back to cited text no. 10
    
11.
Vivarelli M, Moscaritolo E, Tsalkidis A, Massella L, Emma F. Time for initial response to steroids is a major prognostic factor in idiopathic nephrotic syndrome. J Pediatr 2010; 156:965-71.  Back to cited text no. 11
    

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Correspondence Address:
H Barman
Department of Pediatric Disciplines, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong - 793 018
India
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DOI: 10.4103/1319-2442.174198

PMID: 26787586

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